Phosphatidylinositol 3-kinase inhibitors

ABSTRACT

The present application provides the compounds of formula I 
                         
or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein s, t, n, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are as described herein.

FIELD

The present application relates to novel compounds that selectivelyinhibit the activities of PI3K isoforms and their uses in therapeutictreatments.

BACKGROUND

Cell signaling via 3′-phosphorylated phosphoinositides has beenimplicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity(Rameh et al., J. Biol. Chem., 274:8347-8350, 1999).Phosphatidylinositol 3-kinase (PI 3-kinase or PI3K) is responsible forgenerating these phosphorylated signaling products. PI3K was initiallyidentified as a protein associated with viral oncoproteins and growthfactor receptor tyrosine kinases that phosphorylate phosphatidylinositol(PI) and its phosphorylated derivatives at the 3′-hydroxyl of theinositol ring (Panayotou et al., Trends Cell Biol., 2:358-60, 1992).

Three classes of the PI 3-kinase (PI3K) are proposed based on thesubstrate specificities. Class I PI3Ks phosphorylatephosphatidylinositol (PI), phosphatidylinositol-4-phosphate, andphosphatidylinositol-4,5-biphosphate (PIP₂) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Also, Class IIPI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, and ClassIII PI3Ks phosphorylate PI.

The initial purification and molecular cloning of PI 3-kinase revealedthat it was a heterodimer consisting of p85 and p110 subunits (Otsu etal., Cell, 65:91-104, 1991; Hiles et al., Cell, 70:419-29, 1992). Later,four distinct Class I PI3Ks were identified and designated as PI3K α, β,δ, and γ isoforms. Each isoform consists of a distinct 110 kDa catalyticsubunit and a regulatory subunit. The catalytic subunits of PI3K α, β,and δ (i.e., p110α, p110β, and p110δ, respectively) interacts,individually, with the same regulatory subunit p85, whereas thecatalytic subunit of PI3K γ (p110γ) interacts with a distinct regulatorysubunit p101.

Studies have also showed that each PI3K isoform has distinct expressionpattern. For example, PIK3CA which encodes PI3Kα is frequently mutatedin human cancers (Engelman, Nat. Rev. Cancer, 9: 550-562, 2009). Also,PI3Kδ is generally expressed in hematopoietic cells. Moreover, PI3Kisoforms are shown to be associated with proliferation or survivalsignaling in cancers, inflammatory, or autoimmune diseases. As each PI3Kisoform has different biological function, PI3K isoforms are potentialtargets to treat cancer or disorder (U.S. Pat. Nos. 6,800,620;8,435,988; 8,673,906; US Patent Application Publication No.US2013/0274253).

Therefore, there is a need for developing therapeutic agents thatinhibit PI3K isoforms to treat diseases, disorders, or conditions thatare mediated by PI3K.

SUMMARY

The present application provides novel compounds that are inhibitors ofPI3K isoforms. The application also provides compositions, includingpharmaceutical compositions, kits that include the compounds, andmethods of using and making the compounds. The compounds provided hereinare useful in treating diseases, disorders, or conditions that aremediated by PI3K isoforms. The application also provides compounds foruse in therapy. The application further provides compounds for use in amethod of treating a disease, disorder, or condition that is mediated byPI3K isoforms. Moreover, the application provides uses of the compoundsin the manufacture of a medicament for the treatment of a disease,disorder or condition that is mediated by PI3K isoforms. In typicalembodiments, provided are compounds of formula I:

-   wherein n is 1, 2, 3 or 4;-   s is 1 or 2;-   t is 1 or 2;-   each R¹ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰⁰;-   R² is selected from hydrogen, halo, cyano, hydroxy, amino,    —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),    —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g),    —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl    containing 1 to 4 heteroatoms selected from the group consisting of    N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4    heteroatoms selected from the group consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰¹;-   R³ is selected from hydrogen, halo, cyano, hydroxy, amino,    —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),    —N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),    —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a), —S(O)NR^(a)R^(b),    —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a),    —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,    C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms    selected from the group consisting of N, O, and S, and 4-10 membered    heterocyclyl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S;    -   wherein each wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl        and 4-10 membered heterocyclyl is optionally substituted with        one to four R¹⁰²;-   R⁴ is a 5-10 membered heteroaryl;    -   wherein said 5-10 membered heteroaryl is optionally substituted        with one to four R¹⁰³;-   each R⁵ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g), —NR^(a)R^(b), —N(R^(a))C(O)NR^(a)R^(b),    —OC(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a),    —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈    cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4    heteroatoms selected from the group consisting of N, O, and S, and    4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected    from the group consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰⁴;-   each R⁶ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g)—NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl    or C₂₋₆ alkynyl;-   each R^(a) and R^(b) is independently selected from hydrogen, C₆₋₁₀    aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is        optionally substituted with one to four R²⁰⁰;-   each R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ and R¹⁰⁴ is independently selected from    hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl,    —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d),    —N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),    —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a), —S(O)NR^(c)R^(d),    —S(O)₂NR^(c)R^(d), —S(O)R^(g), —S(O)₂R^(g), —NR^(c)R^(d), —OR^(c),    —SR^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,    C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R²⁰¹;    -   each R^(c) and R^(d) is independently selected from hydrogen,        C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   each R²⁰⁰ and R²⁰¹ is independently selected from hydrogen, halo,    cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(f), —N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f),    —S(O)₂NR^(e)R^(f), —S(O)R^(g), —S(O)₂R^(g),    —N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),    —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a), —NR^(e)R^(f), —OR^(e),    —SR^(e), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   each R^(e) and R^(f) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   each R^(g) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl    containing 1 to 4 heteroatoms selected from the group consisting of    N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4    heteroatoms selected from the group consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R²⁰⁰;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, the PI3K inhibitors are the compounds selectedfrom Table 1, a pharmaceutically acceptable salt, isomer, or a mixturethereof. In additional embodiments, the compound is an (S)-enantiomer.In other embodiments, the compound is an (R)-enantiomer. In otheradditional embodiments, the compound is an atropisomer. The applicationalso provides a pharmaceutical composition that comprises a compound offormula (I), a pharmaceutically acceptable salt, isomer, or a mixturethereof, together with at least one pharmaceutically acceptable vehicle.Examples of a pharmaceutically acceptable vehicle may be selected fromcarriers, adjuvants, and excipients.

Further provided herein is a method of treating a disease, disorder, orcondition in a human in need thereof by administering to the human atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt, isomer, or a mixture thereof. Furtherprovided is a compound of formula (I) for use in a method of treating adisease, disorder or condition that is mediated by PI3K isoforms. Theapplication also provides the use of a compound of formula (I) in themanufacture of a medicament for the treatment of a disease, disorder orcondition that is mediated by PI3K isoforms. In certain embodiments, thedisease, disorder, or condition is associated or mediated by PI3K. Insome embodiments, the disease, disorder, or condition is an inflammatorydisorder. In other embodiments, the disease, disorder, or condition is acancer.

Also provided herein is a method of inhibiting the activity of aphosphatidylinositol 3-kinase polypeptide by contacting the polypeptidewith a compound of formula (I) or a pharmaceutically acceptable salt,isomer, or a mixture thereof.

Further provided is a method of inhibiting excessive or destructiveimmune reactions, comprising administering an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt, isomer,or a mixture thereof.

Also provided is a method of inhibiting growth or proliferation ofcancer cells comprising contacting the cancer cells with an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt, isomer, or a mixture thereof.

Also provided is a kit that includes a compound of formula (I) or apharmaceutically acceptable salt, isomer, or a mixture thereof. The kitmay further comprise a label and/or instructions for use of the compoundin treating a disease, disorder, or condition in a human in needthereof. In some embodiments, the disease, disorder, or condition may beassociated or mediated by PI3K activity.

Also provided are articles of manufacture that include a compound offormula (I) or a pharmaceutically acceptable salt, isomer, or a mixturethereof, and a container. In one embodiment, the container may be avial, jar, ampoule, preloaded syringe, or an intravenous bag.

DETAILED DESCRIPTION

The following description sets forth exemplary methods, parameters andthe like. Such description is not intended as a limitation on the scopeof the present application but is instead provided as exemplaryembodiments.

As used herein, the following words, phrases and symbols are generallyintended to have the meanings as set forth below, except to the extentthat the context in which they are used indicates otherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., 1-20 alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named, all geometric isomers having thatnumber of carbons may be encompassed; thus, for example, “butyl”includes n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includesn-propyl and isopropyl.

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(═O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(═O)R^(z), wherein R^(y) and R^(z) are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, haloalkyl, orheteroaryl; each of which may be optionally substituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, or heteroaryl; each of which may be optionallysubstituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one alkenyl). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms ((i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₁₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. By way ofexample, 1, 2 or 3 carbon atoms may be independently replaced with thesame or different heteroatomic group. Heteroatomic groups include, butare not limited to, —NR—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, whereR is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl orheterocycloalkyl, each of which may be optionally substituted. Examplesof heteroalkyl groups include —OCH₃, —CH₂OCH₃, —SCH₃, —CH₂SCH₃, —NRCH₃,and —CH₂NRCH₃, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl,or heteroaryl, each of which may be optionally substituted. As usedherein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms,or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1heteroatom. “Heteroaryl” refers to an aromatic group having a singlering, multiple rings, or multiple fused rings, with one or more ringheteroatoms independently selected from nitrogen, oxygen, and sulfur. Asused herein, heteroaryl include 1 to 20 ring carbon atoms, 3 to 12 ringcarbon atoms, or 3 to 8 carbon ring atoms; and 1 to 5 heteroatoms, 1 to4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen, andsulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl,pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocycloalkyl” refers to a saturated or unsaturated cyclic alkylgroup, with one or more ring heteroatoms independently selected fromnitrogen, oxygen and sulfur. The term “heterocycloalkyl” includesheterocycloalkenyl groups (i.e. the heterocycloalkyl group having atleast one alkenyl). A heterocycloalkyl may be a single ring or multiplerings wherein the multiple rings may be fused, bridged, or spiro. Asused herein, heterocycloalkyl has 2 to 20 ring carbon atoms, 2 to 12ring carbon atoms, 2 to 10 ring carbon atoms, 2 to 8 ring carbon atoms,3 to 12 ring carbon atoms, 3 to 8 ring carbon atoms, or 3 to 6 ringcarbon atoms; and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomindependently selected from nitrogen, sulfur or oxygen. Examples ofheterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl,oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl,cycloalkyl, heterocycloalkyl, heteroaryl, or aryl. Examples of sulfonylare methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Byway of example, there may be one, two, three, four, five, or sixsubstituents. Polymers or similar indefinite structures arrived at bydefining substituents with further substituents appended ad infinitum(e.g., a substituted aryl having a substituted alkyl which is itselfsubstituted with a substituted aryl group, which is further substitutedby a substituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to substituted aryl (substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.For example, the term “substituted aryl” includes, but is not limitedto, “alkylaryl.” Unless specified otherwise, where a group is describedas optionally substituted, any substituents of the group are themselvesunsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, alkoxy,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxy, halo, hydroxyl; “substitutedaryl” refers to an aryl group having one or more substituents includinghalo, alkyl, haloalkyl, heterocycloalkyl, heteroaryl, alkoxy, and cyano,and “substituted sulfonyl” refers to a group —S(O)₂R, in which R issubstituted with one or more substituents of alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl. In other embodiments, the one ormore substituents may be further substituted with halo, alkyl,haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,each of which is substituted. In other embodiments, the substituents maybe further substituted with halo, alkyl, haloalkyl, alkoxy, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted.

Compounds of the invention are named using Chembiodraw Ultra (version14).

List of Abbreviations and Acronyms Abbreviation Meaning ° C. DegreeCelsius Ac Acetyl aq. Aqueous ATP Adenosine triphosphate br Broad BSABovine serum albumin Cbz Carboxybenzyl COD Cyclooctadiene COPD Chronicobstructive pulmonary disease d Doublet DCE Dichloroethene DCMDichloromethane dd Doublet of doublets DIEA Diisopropylethylamine DMFDimethylformamide DMSO Dimethylsulfoxide dt Doublet-triplet DTTDithiothreitol EC₅₀ The half maximal effective concentration eqEquivalents ES/MS Electrospray mass spectrometry Et Ethyl FBS Fetalbovine serum g Grams HEPES2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HPLC Highpressure liquid chromatography hr or h or hrs Hours Hz Hertz IBDInflammatory bowel disease i-pr Isopropyl J Coupling constant (MHz)Kg/kg Kilogram LCMS Liquid chromatography-mass spectrometry LPSLipopolysaccharide M Molar m multiplet M+ Mass peak M + H+ Mass peakplus hydrogen Me Methyl mg Milligram MHz Megahertz ml/mL Milliliter mMMillimolar mmol Millimole MOPS 3-Morpholinopropane-1-sulfonic acid MSMass spectroscopy Ms methanesulfonyl nBu/Bu Butyl nL Nanoliter nmNanometer NMR Nuclear magnetic resonance NMP N-methylpyrrolidinone NP-40Nonyl phenoxypolyethoxylethanol Pd—C/Pd/C Palladium on Carbon Ph Phenylq Quartet q.s. Quantity sufficient to achieve a stated function RPReverse phase rt Room temperature s Singlet sat. Saturated T Triplet TEATriethylamine Tf Trifluoromethanesulfonyl TFA Trifluoroacetic acid THFTetrahydrofuran TR-FRET Time-resolved fluorescence energy transfer δChemical shift (ppm) μL/μl Microliter μM MicromolarCompounds

The present application provides compounds that function as inhibitorsof PI3K isoforms. In one aspect, provided are the compounds having thestructure of Formula I:

-   wherein n is 1, 2, 3 or 4;-   s is 1 or 2;-   t is 1 or 2;-   each R¹ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰⁰;-   R² is selected from hydrogen, halo, cyano, hydroxy, amino,    —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),    —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g),    —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl    containing 1 to 4 heteroatoms selected from the group consisting of    N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4    heteroatoms selected from the group consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰¹;-   R³ is selected from hydrogen, halo, cyano, hydroxy, amino,    —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),    —N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),    —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a), —S(O)NR^(a)R^(b),    —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a),    —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,    C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms    selected from the group consisting of N, O, and S, and 4-10 membered    heterocyclyl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S;    -   wherein each wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl        and 4-10 membered heterocyclyl is optionally substituted with        one to four R¹⁰²;-   R⁴ is a 5-10 membered heteroaryl;    -   wherein said 5-10 membered heteroaryl is optionally substituted        with one to four R¹⁰³;-   each R⁵ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),    —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a), —S(O)NR^(a)R^(b),    —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a),    —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,    C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms    selected from the group consisting of N, O, and S, and 4-10 membered    heterocyclyl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰⁴;-   each R⁶ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl;-   each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆    alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is        optionally substituted with one to four R²⁰⁰;-   each R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ and R¹⁰⁴ is independently selected from    hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl,    —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d),    —N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),    —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a), —S(O)NR^(c)R^(d),    —S(O)₂NR^(c)R^(d), —S(O)R^(c), —S(O)₂R^(c), —NR^(c)R^(d), —OR^(c),    —SR^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,    C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R²⁰¹;    -   each R^(c) and R^(d) is independently selected from hydrogen,        C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   each R²⁰⁰ and R²⁰¹ is independently selected from hydrogen, halo,    cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(f), —N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f),    —S(O)₂NR^(e)R^(f), —S(O)R^(e), —S(O)₂R^(e), —NR^(e)R^(f), —OR^(e),    —SR^(e), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   each R^(e) and R^(f) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   each R^(g) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl    containing 1 to 4 heteroatoms selected from the group consisting of    N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4    heteroatoms selected from the group consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R²⁰⁰;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IA:

-   wherein n, s, t, R¹, R², R⁴, R⁵ and R⁶ are as defined above;-   X¹ is N or C;-   each X², X³, X⁴ and X⁵ is independently selected from S, O, CR¹⁰ and    NR¹¹;    -   wherein each R¹⁰ is independently selected from hydrogen, halo,        cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b),        —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),        —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b),        —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to        4 heteroatoms selected from the group consisting of N, O, and S,        and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms        selected from the group consisting of N, O, and S;        -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈            cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10            membered heterocyclyl is optionally substituted with one to            four R¹⁰⁴;    -   wherein each R¹¹ is independently selected from absent,        hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b),        —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),        —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b),        —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to        4 heteroatoms selected from the group consisting of N, O, and S,        and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms        selected from the group consisting of N, O, and S;-   alternatively, one R¹⁰ and one R¹¹ group, together with the atoms to    which they are attached form a five, six or seven membered fused, or    bridged ring;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IB:

-   wherein n, s, t, R¹, R², R⁴ and R⁵ are as defined above;-   each R¹³ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;-   each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆    alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is        optionally substituted with one to four R²⁰⁰;-   each R²⁰⁰ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(f), —N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f),    —S(O)₂NR^(e)R^(f), —S(O)R^(e), —S(O)₂R^(e), —NR^(e)R^(f), —OR^(e),    —SR^(e), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   each R^(e) and R^(f) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IC:

-   wherein n, s, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula ID:

-   wherein n, s, R¹, R², R⁴, R⁵, X¹, X², X³, X⁴ and X⁵ are as defined    above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IE:

-   wherein n, s, t, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IF:

-   wherein n, s, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IG:

-   wherein n, s, R¹, R², R⁴, R⁵, X¹, X², X³, X⁴ and X⁵ are as defined    above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IH:

-   wherein n, s, t, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IJ:

-   wherein n, s, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula (IK):

-   wherein n, s, R¹, R², R⁵, and R¹³ are as defined above;-   m is 1, 2 or 3;-   each R¹⁴ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl and C₃₋₈ cycloalkyl;-   each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆    alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is        optionally substituted with one to four R²⁰⁰;-   each R²⁰⁰ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(f), —N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f),    —S(O)₂NR^(e)R^(f), —S(O)R^(g), —S(O)₂R^(g), —NR^(e)R^(f), —OR^(e),    —SR^(e), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   each R^(e) and R^(f) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IL:

-   wherein n, m, s, R¹, R², R⁴, R⁵, R¹³ and R¹⁴ are as defined above;-   or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound of Formula I, wherein R³is

-   wherein t is 1 or 2;-   each R¹³ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),    —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula ID or IG, or apharmaceutically acceptable salt, isomer, or a mixture thereof; whereinthe substituent

is selected from:

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ or IK, wherein R⁴ is selected from:

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R¹ is selected from hydrogen,fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl,difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl andtrifluoroethyl; or a pharmaceutically acceptable salt, isomer, or amixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R¹ is fluoro or chloro; or apharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R¹ is fluoro and n is 2.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R² is C₁₋₆ alkyl, C₃₋₈cycloalkyl, 5-6 membered heteroaryl containing 1 to 3 heteroatomsselected from the group consisting of N, O, and S, and 4-6 memberedheterocyclyl containing 1 to 4 heteroatoms selected from the groupconsisting of N, O, and S; wherein each C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocyclyl is optionallysubstituted with one to four R¹⁰¹; or a pharmaceutically acceptablesalt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R² is C₁₋₆ alkyl, C₃₋₈cycloalkyl, or 4-6 membered heterocyclyl containing 1 heteroatomselected from the group consisting of N, O, and S; or a pharmaceuticallyacceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R² is selected from hydrogen,amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,furanyl, tetrahydrofuranyl, oxetanyl, and cyclopropyl; or apharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R⁵ is selected from hydrogen,methyl, ethyl, trifluoromethyl, carboxamide, cyano, piperazinyl,cyclopropyl, phenyl and triazolyl; or a pharmaceutically acceptablesalt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R⁵ is selected from hydrogenor methyl.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK or IL, wherein R¹ is selected from hydrogen,Cl, F and methyl, or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, or IL, wherein R² is selected from hydrogenor a substituent selected from the table below:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound of Formula I, wherein R³is selected from hydrogen or a substituent selected from —C(O)OH,—C(O)NH₂

or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH or IJ, wherein R⁴ is a 5-10 membered heteroarylhaving one or two nitrogens, optionally substituted with one to fourR¹⁰³.

In certain embodiments, R¹⁰³ is selected from cyano, amino, halo, andC₁₋₆ alkyl.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH or IJ, wherein R⁴ is selected from hydrogen or asubstituent selected from the table below:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound selected from Table 1, ora pharmaceutically acceptable salt, isomer, or a mixture thereof:

TABLE 1 Example Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

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28

29

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31

32

33

34

35

36

37

38

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41

42

43

44

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47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

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68

69

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71

72

73

74

75

76

77

78

79

80

81

82

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84

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86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

The present application provides pharmaceutically acceptable salts,hydrates, solvates, isomers, tautomers, stereoisomers, enantiomers,racemates, atropisomers, polymorphs, prodrugs, or a mixture thereof, ofthe compounds described herein. The terms “a compound of the presentapplication,” “a compound described herein,” “a compound of any of theformulae described herein,” or variant thereof refer to a compoundhaving the structure of any of the formulae, I, IA, IB, IC, ID, IE, IF,IG, IH, IJ, IK or IL. In some embodiments, compounds of the presentapplication are Compounds 1-114 as described herein.

“Pharmaceutically acceptable” or “physiologically acceptable” refer tocompounds, salts, compositions, dosage forms and other materials whichare useful in preparing a pharmaceutical composition that is suitablefor veterinary or human pharmaceutical use. “Pharmaceutically acceptablesalts” or “physiologically acceptable salts” refer to salts ofpharmaceutical compounds that retain the biological effectiveness andproperties of the underlying compound, and which are not biologically orotherwise undesirable. There are acid addition salts and base additionsalts. Pharmaceutically acceptable acid addition salts may be preparedfrom inorganic and organic acids. Acids and bases useful for reactionwith an underlying compound to form pharmaceutically acceptable salts(acid addition or base addition salts respectively) are known to one ofskill in the art. Similarly, methods of preparing pharmaceuticallyacceptable salts from an underlying compound (upon disclosure) are knownto one of skill in the art and are disclosed in for example, Berge, atal. Journal of Pharmaceutical Science, January 1977 vol. 66, No. 1, andother sources. If the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Saltsderived from organic acids include acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluene-sulfonic acid, salicylic acid, and the like. Saltsderived from mineral acids include, hydrochloride, hydrobromide,hydroiodide, nitrate, phosphate, and sulfate. Likewise, pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases include, by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

“Isomers” refers to compounds that have the same molecular formula. Asused herein, the term isomers include double bond isomers, racemates,stereoisomers, enantiomers, diastereomers, and atropisomers. Singleisomers, such as enantiomers or diastereomers, can be obtained byasymmetric synthesis or by resolution of a mixture of isomers.Resolution of a mixture of isomers (e.g. racemates) maybe accomplished,for example, by conventional methods such as crystallization in thepresence of a resolving agent, or chromatography, using, for example achiral high pressure liquid chromatography (HPLC) column. “Double bondisomers” refer to Z- and E-forms (or cis- and trans-forms) of thecompounds with carbon-carbon double bonds.

“Atropisomers” refers to conformational stereoisomers which occur whenrotation about a single bond in the molecule is prevented, or greatlyhindered, as a result of steric interactions with other parts of themolecule and the substituents at both ends of the single bond areasymmetrical, i.e., they do not require a stereocenter. Where therotational barrier about the single bond is high enough, andinterconversion between conformations is slow enough, separation andisolation of the isomeric species may be permitted. Atropisomers may beseparated by the methods well known in the art. Unless otherwiseindicated, the description is intended to include individualatropisomers as well as mixtures. Also, as understood by those skilledin the art, the atropisomers may be represented by the same chemicalname with different atropisomer designations. By way of example, thebelow structures are atropisomers of compound 48.

“Racemates” refers to a mixture of enantiomers.

“Stereoisomers” or “stereoisomeric forms” refer to compounds that differin the chirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers. The compounds may exist in stereoisomericform if they possess one or more asymmetric centers or a double bondwith asymmetric substitution and, therefore, can be produced asindividual stereoisomers or as mixtures. Unless otherwise indicated, thedescription is intended to include individual stereoisomers as well asmixtures. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art (see, e.g.,Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wileyand Sons, New York, 1992).

“Tautomers” or “tautomeric forms” refer to alternate forms of a compoundthat differ in the position of a proton, such as enol-keto andimine-enamine tautomers, or heteroaryls such as pyrazoles, imidazoles,benzimidazoles, triazoles, and tetrazoles.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds of any of the formulae describedherein are also provided. Hydrates of the compounds of any of theformulae are also provided.

A “prodrug” is defined in the pharmaceutical field as a biologicallyinactive derivative of a drug that upon administration to the human bodyis converted to the biologically active parent drug according to somechemical or enzymatic pathway. A prodrug is thus a covalently modifiedanalog or latent form of a therapeutically active compound. Non-limitingexamples of prodrugs include ester moieties, quaternary ammoniummoieties, glycol moieties, and the like.

The application also provides a composition containing a mixture ofenantiomers of the compound or a pharmaceutically acceptable saltthereof. In one embodiment, the mixture is a racemic mixture. In otherembodiments, the composition comprises the (S)-enantiomer of a compoundin excess of the corresponding (R)-enantiomer of the compound. In someembodiments, the composition contains the (S)-enantiomer of the compoundand is substantially free of its corresponding (R)-enantiomer. Incertain embodiments, a composition substantially free of the(R)-enantiomer has less than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%,5%, 1%, 0.05%, or 0.01% of the (R)-enantiomer. In other embodiments, thecomposition containing the (S)-enantiomer of a compound or apharmaceutically acceptable salt thereof, predominates over itscorresponding (R)-enantiomer by a molar ratio of at least or about 9:1,at least or about 19:1, at least or about 40:1, at least or about 80:1,at least or about 160:1, or at least or about 320:1.

The composition containing a compound according to any of the formulaedescribed herein or a pharmaceutically acceptable salt thereof, may alsocontain the compound in enantiomeric excess (e.e.). By way of example, acompound with 95% (S)-isomer and 5% (R)-isomer will have an e.e. of 90%.In some embodiments, the compound has an e.e. of at least or about 60%,75%, 80%, 85%, 90%, 95%, 98% or 99%.

In any one of the foregoing embodiments, the compound or apharmaceutically acceptable salt thereof, is an atropisomer. Anotherembodiment provides the composition containing a mixture of atropisomersof the compound or a pharmaceutically acceptable salt thereof. By way ofexample, a compound with 95% of one atropisomer and 5% of the otheratropisomers. In some embodiments, a compound with about 90, 80, 70, 60,50, 40, 30, 20, or 10% of one atropisomer and 10, 20, 30, 40, 50, 60,70, 80, or 90%, respectively, of the other atropisomers.

The application also provides the free base forms of the compoundsdescribed herein. In certain embodiments, provided herein are theenantiomers, (R) or (S), of the compounds of the formulae describedherein. In other embodiments, provided herein are the atropisomers ofthe compounds of the formulae described herein.

The application further provides compositions comprising the compoundsdescribed herein or a pharmaceutically acceptable salt, isomer, prodrug,or solvate thereof. The composition may include racemic mixtures,mixtures containing an enantiomeric excess of one enantiomer or singlediastereomers or diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included herein, the same as if each andevery isomeric form were specifically and individually listed.

In certain embodiments, provided herein are also polymorphs, such ascrystalline and amorphous forms, of the compounds described herein. Insome embodiments, provided are also chelates, non-covalent complexes,and mixtures thereof, of the compounds of the formula described hereinor pharmaceutically acceptable salts, prodrugs, or solvates thereof. A“chelate” is formed by the coordination of a compound to a metal ion attwo (or more) points. A “non-covalent complex” is formed by theinteraction of a compound and another molecule wherein a covalent bondis not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds described herein or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof. A “chelate” isformed by the coordination of a compound to a metal ion at two (or more)points. A “non-covalent complex” is formed by the interaction of acompound and another molecule wherein a covalent bond is not formedbetween the compound and the molecule. For example, complexation canoccur through van der Waals interactions, hydrogen bonding, andelectrostatic interactions (also called ionic bonding).

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labeled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogs” of compounds ofFormula I in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I when administered to a mammal, particularly a human. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosuremay have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

Therapeutic Uses of the Compounds

The compounds of the formulae described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, or solvate thereof may be used for thetreatment of diseases and/or conditions mediated by PI3K isoforms. Inaddition, the application provides the compounds for use in therapy.Also, provided herein are methods for inhibiting one or more PI3Kisoforms. In one embodiment, provided are methods for inhibiting PI3Kβactivity using the compound described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, or solvate thereof. In otherembodiment, provided are methods for inhibiting PI3Kβ activities usingthe compound or a pharmaceutically acceptable salt, isomer, prodrug, orsolvate thereof. The application further provides methods for use insuch methods. The PI3K isoforms may be selectively or specificallyinhibited. Additionally, the compounds may be used to inhibit PI3Kactivity therapeutically or prophylactically, such as PI3Kβ.

The compounds according to the present application may be used incombination with one or more additional therapeutic agents. Thetherapeutic agents may be in the forms of compounds, antibodies,polypeptides, or polynucleotides. The therapeutic agent includes, but isnot limited to, a chemotherapeutic agent, an immunotherapeutic agent, aradiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent,an anti-proliferation agent, an anti-fibrotic agent, an anti-angiogenicagent, a therapeutic antibody, or any combination thereof. In oneembodiment, the application provides a product comprising a compounddescribed herein and an additional therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in therapy,e.g. a method of treating a disease, disorder, or condition that ismediated by PI3K isoforms. The compounds of the invention can be used incombination with compounds that inhibit or modulate the activities ofpoly(ADP-ribose) polymerases (PARP), such as PARP-1, PARP-2, PARP-3 andVault-PARP; Tankyrases (TANKs), such as, TANK-1, TANK-2 and TANK-3;matrix metalloproteinases such as MMP-2 and MMP-9; and androgenreceptor.

Therapeutic agents that can be used in combination with compounds of theinvention include enzalutamide, abiraterone, abiraterone acetate,apalutamide, galeterone, olaparib, niraparib, veliparib, rucaparib,flutamide, nilutamide, bicalutamide, ketonazole, orteronel, finasteride,dutasteride, bexlosteride, izonsteride, turosteride, episteride,dexamethasone, prednisone, leuprolide, goserelin, triptorelin,histrelin, estrogen, cyproterone acetate, spironolactone, flutamide,hydroxyflutamide, docetaxel, cabazitaxel, sipuleucel-T, ODM-201, VT-464,EPI-506, and combinations thereof.

Also, the therapeutic agents may be those that inhibit or modulate theactivities of Bruton's tyrosine kinase, spleen tyrosine kinase,apoptosis signal-regulating kinase, Janus kinase, lysyl oxidase, lysyloxidase-like proteins, matrix metallopeptidase, bromodomain-containingprotein, adenosine A2B receptor, isocitrate dehydrogenase,serine/threonine kinase TPL2, discoidin domain receptor,serine/threonine-protein kinases, IKK, MEK, EGFR, histone deacetylase,protein kinase C, or any combination thereof. In certain embodiments,the therapeutic agent may be selected from a PI3K (including PI3Kγ,PI3Kδ, PI3Kβ, PI3Kα, and/or pan-PI3K) inhibitor, a JAK (Janus kinase,including JAK1, JAK2, and/or JAK3) inhibitor, a SYK (spleen tyrosinekinase) inhibitor, a BTK (Bruton's tyrosine kinase) inhibitor, an A2B(adenosine A2B receptor) inhibitor, an ACK (activated CDC kinase,including ACK1) inhibitor, an ASK (apoptosis signal-regulating kinase,including ASK1) inhibitor, Aurora kinase, a BRD (bromodomain-containingprotein, including BRD4) inhibitor, a Bcl (B-cell CLL/lymphoma,including Bcl-1 and/or Bcl-2) inhibitor, a CAK (CDK-activating kinase)inhibitor, a CaMK (calmodulin-dependent protein kinases) inhibitor, aCDK (cyclin-dependent kinases, including CDK1, 2, 3, 4, and/or 6)inhibitor, a CK (casein kinase, including CK1 and/or CK2) inhibitor, aDDR (discoidin domain receptor, including DDR1 and/or DDR2) inhibitor, aEGFR inhibitor, a FXR (farnesoid×receptor) inhibitor, a FAK (focaladhesion kinase) inhibitor, a GSK (glycogen synthase kinase) inhibitor,a HDAC (histone deacetylase) inhibitor, an IDO (indoleamine2,3-dioxygenase) inhibitor, an IDH (isocitrate dehydrogenase, includingIDH1) inhibitor, an IKK (1-Kappa-B kinase) inhibitor, a KDMS (lysinedemethylase) inhibitor, a LCK (lymphocyte-specific protein tyrosinekinase) inhibitor, a LOX (lysyl oxidase) inhibitor, a LOXL (lysyloxidase like protein, including LOXL1, LOXL2, LOXL3, LOXL4, and/orLOXL5) inhibitor, a MTH (mut T homolog) inhibitor, a MEK(mitogen-activated protein kinase kinase) inhibitor, a matrixmetalloprotease (MMP, including MMP2 and/or MMP9) inhibitor, amitogen-activated protein kinases (MAPK) inhibitor, a PD-1 (programmedcell death protein 1) inhibitor, a PD-L1 (programmed death-ligand 1)inhibitor, a PDGF (platelet-derived growth factor) inhibitor, aphosphorylase kinase (PK) inhibitor, a PLK (polo-like kinase, includingPLK1, 2, 3) inhibitor, a protein kinase (PK, including protein kinase A,B, C) inhibitor, a STK (serine/threonine kinase) inhibitor, a STAT(signal transduction and transcription) inhibitor, aserine/threonine-protein kinase inhibitor, a TBK (tank-binding kinase)inhibitor, a TLR (toll-like receptor modulators, including TLR-1, TLR-2,TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12,and/or TLR-13) inhibitor, a TK (tyrosine kinase) inhibitor, a TPL2(serine/threonine kinase) inhibitor, a NEK9 inhibitor, an Abl inhibitor,a p38 kinase inhibitor, a PYK inhibitor, a PYK inhibitor, a c-Kitinhibitor, a NPM-ALK inhibitor, a Flt-3 inhibitor, a c-Met inhibitor, aKDR inhibitor, a TIE-2 inhibitor, a VEGFR inhibitor, a SRC inhibitor, aHCK inhibitor, a LYN inhibitor, a FYN inhibitor, a YES inhibitor, achemotherapeutic agent, an immunotherapeutic agent, a radiotherapeuticagent, an anti-neoplastic agent, an anti-cancer agent, ananti-proliferation agent, an anti-fibrotic agent, an anti-angiogenicagent, a therapeutic antibody, or any combination thereof. In someembodiments, the JAK inhibitor isN-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide asnamed by ChemDraw (may also be referred to as CYT0387 or momelotinib)and may be synthesized by the methods described in U.S. Pat. No.8,486,941. In certain embodiment, the SyK inhibitor is6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amineas named by ChemDraw (may also be referred to as6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-amine)and may be synthesized by the methods described in U.S. Pat. No.8,450,321. In other embodiments, the BTK inhibitor is(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-oneas named by ChemDraw (may also be6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one)and may be synthesized by the methods in U.S. Pat. No. 8,557,803.

Chemotherapeutic agents may be categorized by their mechanism of actioninto, for example, the following groups: anti-metabolites/anti-canceragents, such as pyrimidine analogs (floxuridine, capecitabine, andcytarabine); purine analogs, folate antagonists and related inhibitors,antiproliferative/antimitotic agents including natural products such asvinca alkaloid (vinblastine, vincristine) and microtubule such as taxane(paclitaxel, docetaxel), vinblastin, nocodazole, epothilones andnavelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damagingagents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil,cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin,doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine,mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere,teniposide, etoposide, triethylenethiophosphoramide); antibiotics suchas dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards cyclophosphamide and analogs, melphalan, chlorambucil), and(hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) andanalogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,goserelin, bicalutamide, nilutamide) and aromatase inhibitors(letrozole, anastrozole); anticoagulants (heparin, synthetic heparinsalts and other inhibitors of thrombin); fibrinolytic agents (such astissue plasminogen activator, streptokinase and urokinase), aspirin,dipyridamole, ticlopidine, clopidogrel; antimigratory agents;antisecretory agents (breveldin); immunosuppressives (tacrolimus,sirolimus azathioprine, mycophenolate); phytoestrogens (daidzein,glycitein, genisteinand growth factor inhibitors (vascular endothelialgrowth factor inhibitors, fibroblast growth factor inhibitors);angiotensin receptor blocker, nitric oxide donors; anti-senseoligonucleotides; antibodies (trastuzumab, rituximab); cell cycleinhibitors and differentiation inducers (tretinoin); inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin,dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecanand mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids(cortisone, dexamethasone, hydrocortisone, methylprednisolone,prednisone, and prednisolone); growth factor signal transduction kinaseinhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin,Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, ordiphtheria toxin, and caspase activators; and chromatin.

As used herein the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy,” in the case of treatment with a chemotherapeuticagent) is meant to encompass any non-proteinaceous (i.e., non-peptidic)chemical compound useful in the treatment of cancer. Examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; emylerumines and memylamelamines includingalfretamine, triemylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimemylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingsynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (articularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, foremustine, lomustine, nimustine,ranimustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1,see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromomophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as demopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogues such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replinisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine;maytansinoids such as maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethane; vindesine;dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids,e.g., paclitaxel (TAXOL® and docetaxel (TAXOTERE®); chlorambucil;gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine;vinorelbine (Navelbine®); novantrone; teniposide; edatrexate;daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, andirinotecan) and pharmaceutically acceptable salts, acids or derivativesof any of the above. One or more chemotherapeutic agent are used orincluded in the present application.

Also included in the definition of “chemotherapeutic agent” areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including Nolvadex™),raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene,LY117018, onapristone, and toremifene (Fareston®); inhibitors of theenzyme aromatase, which regulates estrogen production in the adrenalglands, such as, for example, 4(5)-imidazoles, aminoglutethimide,megestrol acetate (Megace®), exemestane, formestane, fadrozole, vorozole(Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®.); andanti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde,and goserelin; and pharmaceutically acceptable salts, acids orderivatives of any of the above.

The anti-angiogenic agents include, but are not limited to, retinoidacid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®,ENDOSTATIN®, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproternase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism, including for example, proline analogs((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline,d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpba-2-antiplasmin, bisantrene, lobenzarit disodium,n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide; angiostatic steroid, carboxynaminoimidazole;metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents include antibodies, preferably monoclonal antibodies againstthese angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGFisoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K.“Clinical application of angiogenic growth factors and their inhibitors”(1999) Nature Medicine 5:1359-1364.

The anti-fibrotic agents include, but are not limited to, the compoundssuch as beta-aminoproprionitrile (BAPN), as well as the compoundsdisclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct.23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitorsof lysyl oxidase and their use in the treatment of diseases andconditions associated with the abnormal deposition of collagen; U.S.Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled“Anti-fibrotic agents and methods for inhibiting the activity of lysyloxidase in situ using adjacently positioned diamine analogue substrate,”relating to compounds which inhibit LOX for the treatment of variouspathological fibrotic states, which are herein incorporated byreference. Further exemplary inhibitors are described in U.S. Pat. No.4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled“Inhibitors of lysyl oxidase,” relating to compounds such as2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g.,U.S. Pat. Nos. 5,021,456; 5,5059,714; 5,120,764; 5,182,297; 5,252,608(relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. PatentApplication No. 2004/0248871, which are herein incorporated byreference. Exemplary anti-fibrotic agents also include the primaryamines reacting with the carbonyl group of the active site of the lysyloxidases, and more particularly those which produce, after binding withthe carbonyl, a product stabilized by resonance, such as the followingprimary amines: emylenemamine, hydrazine, phenylhydrazine, and theirderivatives, semicarbazide, and urea derivatives, aminonitriles, such asbeta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated orsaturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine,2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines,selenohomocysteine lactone. Also, the anti-fibrotic agents are copperchelating agents, penetrating or not penetrating the cells. Exemplarycompounds include indirect inhibitors such compounds blocking thealdehyde derivatives originating from the oxidative deamination of thelysyl and hydroxylysyl residues by the lysyl oxidases, such as thethiolamines, in particular D-penicillamine, or its analogues such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate,sodium-4-mercaptobutanesulphinate trihydrate.

The immunotherapeutic agents include and are not limited to therapeuticantibodies suitable for treating patients; such as abagovomab,adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab,anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab,bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab,cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab,daratumumab, drozitumab, duligotumab, dusigitumab, detumomab,dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab,ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab,lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab,matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab,narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn,ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab,oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab,pertuzumab, pintumomab, pritumumab, racotumomab, radretumab,rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab,siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab,tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab,tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab,zalutumumab, obinutuzumab, CC49 and 3F8. The exemplified therapeuticantibodies may be further labeled or combined with a radioisotopeparticle, such as indium In 111, yttrium Y 90, iodine I-131.

The application also provides method for treating a subject who isundergoing one or more standard therapies, such as chemotherapy,radiotherapy, immunotherapy, surgery, or combination thereof.Accordingly, one or more therapeutic agent or inhibitors may beadministered before, during, or after administration of chemotherapy,radiotherapy, immunotherapy, surgery or combination thereof.

Other examples of chemotherapy treatments (including standard orexperimental chemotherapies) are described below. In addition, treatmentof certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P.,“Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The NewEngland Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G.,“Current and Investigational Therapies for Patients with CLL” Hematology2006, p. 285-294. Lymphoma incidence patterns in the United States isprofiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHOSubtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.

Examples of immunotherapeutic agents include, but are not limited to,rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath),anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies,anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies,apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab,milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine,WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derivedHSPPC-96, and veltuzumab. Additional immunotherapy agents includes usingcancer vaccines based upon the genetic makeup of an individual patient'stumor, such as lymphoma vaccine example is GTOP-99 (MyVax®).

Examples of chemotherapy agents include aldesleukin, alvocidib,antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin,amifostine trihydrate, aminocamptothecin, arsenic trioxide, betaalethine, Bcl-2 family protein inhibitor ABT-263, ABT-199, BMS-345541,bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H,CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin,Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine,Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine,denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10,Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride,enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide,filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara),Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride,ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activatedkiller cells, melphalan, methotrexate, mitoxantrone hydrochloride,motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen(Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate,omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylatedliposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent),perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202),recombinant interferon alfa, recombinant interleukin-12, recombinantinterleukin-11, recombinant flt3 ligand, recombinant humanthrombopoietin, rituximab, sargramostim, sildenafil citrate,simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin,Temsirolimus (CC1-779), Thalidomide, therapeutic allogeneic lymphocytes,thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine(Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat(SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone), CVP(cyclophosphamide, vincristine and prednisone), FCM (fludarabine,cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide,rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine,doxorubicin, dexamethasone, methotrexate, cytarabine), ICE(iphosphamide, carboplatin and etoposide), MCP (mitoxantrone,chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP(rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE),and R-MCP (R-MCP).

The therapeutic treatments can be supplemented or combined with any ofthe abovementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine I-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®),Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem celltransplantation, autologous hematopoietic stem cell transplantation,autologous bone marrow transplantation, antibody therapy, biologicaltherapy, enzyme inhibitor therapy, total body irradiation, infusion ofstem cells, bone marrow ablation with stem cell support, invitro-treated peripheral blood stem cell transplantation, umbilical cordblood transplantation, immunoenzyme technique, pharmacological study,low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery,radiation therapy, and nonmyeloablative allogeneic hematopoietic stemcell transplantation.

In some embodiments, the methods include administering a compound of theformula described herein or a pharmaceutically acceptable salt, isomer,prodrug, or solvate thereof, in a therapeutically effective amount to ahuman in need thereof. The method can be employed to treat a patient whohas or is believed to have a disease or condition whose symptoms orpathology is mediated by expression or activity of PI3Kβ. The patientmay be a mammal or a human. In certain embodiment, the patient may be ahuman.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing theeffect of another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” or “patient” refer to an animal, such as a mammal (including ahuman), that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human “Human in needthereof” refers to a human who may have or is suspect to have diseases,or disorders, or conditions that would benefit from certain treatment;for example, being treated with the PI3K inhibitor of the compoundsaccording to the present application. In certain embodiments, thesubject may be a human who (i) has not received any treatment includingchemotherapy treatment, (ii) is substantially refractory to at least onechemotherapy treatment, (iii) is in relapse after treatment withchemotherapy, or both (i) and (ii). In some of embodiments, the subjectis refractory to at least one, at least two, at least three, or at leastfour chemotherapy treatments (including standard or experimentalchemotherapies).

The terms “therapeutically effective amount” or “effective amount” of acompound of the present application or a pharmaceutically acceptablesalt, isomers, prodrug, or solvate thereof, mean an amount sufficient toeffect treatment when administered to a subject, to provide atherapeutic benefit such as amelioration of symptoms or slowing ofdisease progression. For example, a therapeutically effective amount maybe an amount sufficient to decrease a symptom of a disease or conditionresponsive to inhibition of PI3Kδ and PI3Kβ activity. Thetherapeutically effective amount may vary depending on the subject, anddisease or condition being treated, the weight and age of the subject,the severity of the disease or condition, and the manner ofadministering, which can readily be determined by one or ordinary skillin the art.

In addition to the therapeutic uses, the compounds described herein havethe selectivity or selective inhibition to certain PI3K isoforms. In oneembodiment, the compounds have selectivity to PI3Kβ. The selectivity toPI3K isoforms may be determined by measuring the compound's activity ininhibiting certain PI3K isoforms using the assay described in theexample below or the methods commonly used. It is understood that theconditions (e.g. the reagent concentration or the incubationtemperature) may be varied and the results of the assay may vary. Insome instances, the value may vary within a range of one to three-fold.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. The term “inhibition of activity of PI3Kisoforms” or variants thereof refer to a decrease in activity in anyPI3K isoform (e.g., alpha, beta, gamma, or delta) as a direct orindirect response to the presence of a compound of any of the formuladescribed herein relative to the activity of PI3K isoform in the absenceof such compound. “Inhibition of PI3Kδ and/or PI3Kβ activities” orvariants thereof refer to a decrease in PI3Kδ and/or PI3Kβ activities asa direct or indirect response to the presence of the compounds describedherein, relative to the activities of PI3Kδ and/or PI3Kβ in the absenceof such compound. In some embodiments, the inhibition of PI3K isoformactivities may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

Without being bound to any theory, the decrease in the activity of PI3Kmay be due to the direct interaction of the compound with PI3K, or dueto the interaction of the compounds described herein with one or moreother factors that affect PI3K activity. For example, the presence ofthe compounds may decrease the activities of PI3Kδ and/or PI3Kβ bydirectly binding to PI3Kδ and/or PI3Kβ, by causing (directly orindirectly) another factor to decrease PI3Kδ and/or PI3Kβ activities, orby (directly or indirectly) decreasing the amount of PI3Kδ and/or PI3Kβpresent in the cell or organism.

The term “PI3K inhibitor” or variant thereof refers to a compound thatinhibits the activity of PI3K. The term “PI3K isoform selectiveinhibitor” or variant thereof refers to a compound that inhibits theactivity of one or more PI3K isoforms more effectively than the otherremaining PI3K isoforms. By way of example, the term “PI3Kβ selectiveinhibitor” generally refers to a compound that inhibits the activity ofthe PI3Kβ isoform more effectively than other isoforms of the PI3Kfamily, and the term “PI3Kδ selective inhibitor” generally refers to acompound that inhibits the activity of the PI3Kδ isoform moreeffectively than other isoforms of the PI3K family. The term “dualPI3Kδ/β selective inhibitor” generally refers to a compound thatinhibits the activity of both PI3Kδ and PI3Kβ isoforms more effectivelythan other isoforms of the PI3K family (e.g., PI3K α or γ).

The relative efficacies of compounds as inhibitors of an enzyme activity(or other biological activity) can be established by determining theconcentrations at which each compound inhibits the activity to apredefined extent and then comparing the results. In one embodiment, theefficacy of a compound as an inhibitor of one or more PI3K isoforms canbe measured by the compound concentration that inhibits 50% of theactivity in a biochemical assay, i.e., the 50% inhibitory concentrationor “IC₅₀”. The determination of IC₅₀ values can be accomplished usingconventional techniques known in the art, including the techniquesdescribed in the Examples below. In general, an IC₅₀ can be determinedby measuring the activity of a given enzyme in the presence of a rangeof concentrations of the compound under the study. The experimentallyobtained values of enzyme activity may then be plotted against thecompound concentrations used. The concentration of the inhibitor thatshows 50% enzyme activity (as compared to the activity in the absence ofany inhibitor) is taken as the IC₅₀ value. Analogously, other inhibitoryconcentrations can be defined through appropriate determinations ofactivity. For example, in some settings it may be desirable to establisha 90% inhibitory concentration, i.e., IC₉₀.

According to the present application, a PI3Kβ selective inhibitor is acompound that exhibits a 50% inhibitory concentration (IC₅₀) withrespect to PI3Kβ that is at least 10-fold, at least 20-fold, at least30-fold, at least 50-fold, at least 100-fold, at least 200-fold, or atleast 500-fold lower than the IC₅₀ with respect to either PI3Kα or PI3Kγor both PI3Kα and PI3Kγ. In addition, a PI3Kδ/β selective inhibitor is acompound that exhibits a 50% inhibitory concentration (IC₅₀) withrespect to PI3Kβ and PI3Kδ that is at least 10-fold, at least 20-fold,at least 30-fold, at least 50-fold, at least 75-fold, at least 100-fold,at least 200-fold, and at least 500-fold lower than the IC₅₀ withrespect to either PI3Kα or PI3Kγ. The dual PI3Kδ/β selective inhibitormay have the same or similar IC₅₀ to both PI3Kδ and PI3Kβ or may havedifferent IC₅₀ to either PI3Kδ or PI3Kβ. As used herein, the term“potency,” “potent,” or variants thereof refer to the compoundexhibiting an IC₅₀ value that is less than 100 nM. When comparing twocompounds, the compound that exhibits a lower IC₅₀ value is referred toas a more potent inhibitor.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the compounds may be usedfor a variety of purposes, including therapeutic and experimentalpurposes. For example, it may be used ex vivo to determine the optimalschedule and/or dosing of administration of a PI3K selective inhibitorfor a given indication, cell type, individual, and other parameters.Information gleaned from such use may be used for experimental purposesor in the clinic to set protocols for in vivo treatment. Other ex vivouses for which the compound described herein may be suited are describedbelow or will become apparent to those skilled in the art. The compoundsof the formula described herein or a pharmaceutically acceptable salt,prodrug, or solvate thereof, may be further characterized to examine thesafety or tolerance dosage in human or non-human subjects. Suchproperties may be examined using commonly known methods to those skilledin the art.

Compared to other PI3K isoforms, PI3Kβ is generally mis-regulated incertain cancer cells. Aberrant proliferation of cells often interfereswith normal tissue function, which may result in abnormal cellularresponse such as immunity, inflammation, and/or apoptosis. The selectiveinhibitors to PI3Kβ are useful in treating, inhibiting, or preventingaberrant proliferation of cancerous and/or hematopoietic cells andameliorating the symptoms and secondary conditions.

The compounds described herein may be used to treat subjects havingvarious disease states, disorders, and conditions (also collectivelyreferred to as “indications”) associated with PI3K isoforms or theiractivities. As used herein, the terms “diseases,” “disorders,”“conditions” are used interchangeably. Such indications may include, forexample, cancer, including hematologic malignancies (e.g. leukemias andlymphomas, myeloproliferative disorders, myelodysplastic syndromes,plasma cell neoplasms) and solid tumors, inflammation, fibrosis,allergic conditions (including hypersensitivity), cardiovasculardiseases, neurodegenerative diseases, renal disorders, viral infections,obesity, and autoimmune diseases.

In other embodiments, the compounds described herein may be used totreat cancers that are mediated by, dependent on, or associated withPI3K activity. In certain embodiments, the disease or condition is anautoimmune disease, an inflammatory disease, or a cancer. In someembodiments, the disease or condition is chosen from rheumatoidarthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupuserythematosus, multiple sclerosis, inflammatory bowel disease, asthma,chronic obstructive airways disease, pneumonitis, dermatitis, alopecia,nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis,primary biliary cirrhosis, sclerosing cholangitis, diabetes (includingtype I diabetes), acute rejection of transplanted organs, lymphomas,multiple myelomas, leukemias, neoplasms and solid tumors.

In other embodiments, the disease is a solid tumor. By way of examples,the solid tumor includes but is not limited to prostate cancer,(including castration-resistant prostate cancer), pancreatic cancer,bladder cancer, colorectal cancer, breast cancer, renal cancer,hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer,rectum cancer, liver cancer, kidney cancer, stomach cancer, skin cancer,gastric cancer, esophageal cancer, head and neck cancer, melanoma,neuroendocrine cancers, CNS cancers (e.g., neuroblastoma), brain tumors(e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, or softtissue sarcoma. In some embodiments, the solid tumor is non-small celllung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma,ovarian cancer, renal cancer, pancreatic cancer, prostate cancer, orbreast cancer.

The present application also provides a method for treating a human inneed thereof, who has or is suspected of having a disease or conditionresponsive or believed to be responsive to the inhibition PI3Kβ activityby administering to the subject a compound of the formulae describedherein or a pharmaceutically acceptable salt, enantiomer, atropisomer,tautomer, prodrug, or solvate thereof.

Additionally, the application provides a method of inhibiting kinaseactivity of a PI3Kβ polypeptides by contacting the polypeptides with acompound of the formulae described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, solvate, or a mixture thereof.

Moreover, the application provides a method of decreasing cellviability, increasing cell death or apoptosis, increasing interferencewith PI3K signaling pathways (including AKT, S6RP, ERK phosphorylation),and/or reduction in chemokine production with an effective amount of acompound of any of the formulae described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, solvate, or a mixture thereof.

The application further provides a method of disrupting leukocytefunction comprising contacting the leukocytes with an effective amountof a compound of any of the formulae described herein or apharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixturethereof, in a human in need thereof.

Provided is also a method of inhibiting growth or proliferation ofcancer cells comprising contacting the cancer cells with an effectiveamount of a compound of the formulae described herein or apharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixturethereof.

Kits

Provided herein are also kits that include a compound of the formulae ofthe present application or a pharmaceutically acceptable salt, isomer,prodrug, or solvate thereof, and suitable packaging. In one embodiment,a kit further includes instructions for use. In one aspect, a kitincludes a compound of the formulae described herein or apharmaceutically acceptable salt, isomer, prodrug, or solvate thereof,and a label and/or instructions for use of the compounds in thetreatment of the indications, including the diseases or conditions,described herein.

Provided herein are also articles of manufacture that include a compoundof any of the formulae described herein or a pharmaceutically acceptablesalt, isomer, prodrug, or solvate thereof, in a suitable container. Thecontainer may be a vial, jar, ampoule, preloaded syringe, andintravenous bag.

Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provides herein are alsopharmaceutical compositions that contain one or more of the compounds ofany of the formulae disclosed herein or a pharmaceutically acceptablesalt, isomers, prodrug, or solvate thereof, and one or morepharmaceutically acceptable vehicles selected from carriers, adjuvantsand excipients. Suitable pharmaceutically acceptable vehicles mayinclude, for example, inert solid diluents and fillers, diluents,including sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants. Such compositions areprepared in a manner well known in the pharmaceutical art. See, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant. In someembodiments, the pharmaceutical composition is administered orally.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound of any of the formulaedescribed herein or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, the active ingredient is usually diluted by anexcipient and/or enclosed within such a carrier that can be in the formof a capsule, sachet, paper or other container. When the excipientserves as a diluent, it can be in the form of a solid, semi-solid, orliquid material, which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing, for example, up to 10% by weight of theactive compound, soft and hard gelatin capsules, sterile injectablesolutions, and sterile packaged powders. In certain embodiments, thepharmaceutical composition is in the form of tablets.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound of any of theformulae described herein or a pharmaceutically acceptable salt, isomer,prodrug, or solvate thereof, can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the subject by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds described herein in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of any of the above formulae or a pharmaceutically acceptablesalt, prodrug, or solvate thereof. When referring to thesepreformulation compositions as homogeneous, the active ingredient may bedispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

Dosing

The specific dose level of a compound of the formulae described hereinfor any particular subject will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound of the formula per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.01 and 200 mg/kg may be appropriate.In some embodiments, about 0.01 and 150 mg/kg may be appropriate. Inother embodiments a dosage of between 0.05 and 100 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compoundof the formulae administered per dose or per day. Daily dosage of acompound may be between about 1 mg and 2,000 mg, between about 1,000 to2,000 mg/day, between about 1 to 1,000 mg/day, between about 1 to 500mg/day, between about 100 to 150 mg/day, between about 1 to 100 mg/day,between about between about 1 to 50 mg/day, between about 50 to 100mg/day, between about 100 to 125 mg/day, between about 100 to 150mg/day, between about 100 to 175 mg/day, between about 100 to 200mg/day, between about 100 to 225 mg/day, between about 100 to 250mg/day, between about 100 to 350 mg/day, between about 100 to 400mg/day, between about 100 to 450 mg/day, or between about 100 to 500mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg/day, between about 1 to 100 mg/day, betweenabout 1 to 50 mg/day, between about 50 to 100 mg/day, between 50 to 300mg/day, between 50 to 200 mg/day, between 75 to 200 mg/day, between 75to 150 mg/day, between 100 to 200 mg/day, between about 200 to 300mg/day, between about 300 to 400 mg/day, between about 400 to 500mg/day, between about 100 to 150 mg/day, between about 150 to 200mg/day, between about 200 to 250 mg/day, between about 75 to 150 mg/day,or between about 150 to 300 mg/day.

The compounds of the present application or the compositions thereof maybe administered once, twice, three, or four times daily, using anysuitable mode described above. Also, administration or treatment withthe compounds according to any of the formulae described herein may becontinued for a number of days; for example, commonly treatment wouldcontinue for at least 7 days, 14 days, or 28 days, for one cycle oftreatment. In some treatment, the compound or the composition thereof isadministered continuously, i.e. every day. Treatment cycles are wellknown in cancer chemotherapy, and are frequently alternated with restingperiods of about 1 to 28 days, commonly about 7 days or about 14 days,between cycles. The treatment cycles, in other embodiments, may also becontinuous.

In a particular embodiment, the method comprises administering to thesubject an initial daily dose of about 1 to 500 mg of a compound of theabove formula and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 1, 5, 10, 25, 50, 75, or 100mg can be used to increase the dose. The dosage can be increased daily,every other day, twice per week, or once per week.

Synthesis of the Compounds

The compounds of the present application may be prepared using themethods disclosed herein and routine modifications thereof, which willbe apparent given the disclosure herein and methods well known in theart. Conventional and well-known synthetic methods may be used inaddition to the teachings herein. The synthesis of typical compoundsdescribed herein may be accomplished as described in the followingexamples. If available, reagents may be purchased commercially, e.g.,from Sigma Aldrich or other chemical suppliers. In general, compoundsdescribed herein are typically stable and isolatable at room temperatureand pressure.

General Synthesis

Typical embodiments of compounds described herein may be synthesizedusing the general reaction schemes described below. It will be apparentgiven the description herein that the general schemes may be altered bysubstitution of the starting materials with other materials havingsimilar structures to result in products that are correspondinglydifferent. Descriptions of syntheses follow to provide numerous examplesof how the starting materials may vary to provide correspondingproducts. Given a desired product for which the substituent groups aredefined, the necessary starting materials generally may be determined byinspection. Starting materials are typically obtained from commercialsources or synthesized using published methods. For synthesizingcompounds which are embodiments described in the present disclosure,inspection of the structure of the compound to be synthesized willprovide the identity of each substituent group. The identity of thefinal product will generally render apparent the identity of thenecessary starting materials by a simple process of inspection, giventhe examples herein.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, and the like). Unless specified to the contrary, the solventsused in the reactions of the present invention are inert organicsolvents, and the reactions are carried out under an inert gas,preferably nitrogen or argon.

The compounds of formula (IM) may be prepared using the method similarto the Reaction Scheme I shown below:

Step 1—Preparation of a Compound of Formula (1)

The compounds of formula (1) can be made by combining compounds (A) and(B). Compounds (A) and (B) are commercially available or can be made bymethods known in the art. With respect to compound (A), Y¹ is Cl, Br orneopentylglycolatoboron. With respect to compound (B), R³⁰ and R³¹ areindependently selected from R¹⁰³ or B(OH)₂; and, X⁶ and X⁷ areindependently selected from N and CR¹⁰³ wherein R¹⁰³ is as definedabove. Compounds (A) and (B) can be mixed in the presence of a catalystsuch as tetrakis(triphenylphosphine)palladium(0) and a base such aspotassium phosphate tribasic in a suitable solvent such as a mixture ofdioxane and water. After further stirring at a temperature between 70and 110° C. for between 1 and 24 hours, the reaction mixture is allowedto cool to room temperature. To extract the compound of formula (1), anorganic solvent such as ethyl acetate may be added, followed by washingwith water and brine. The organic phase can be concentrated to obtainthe compound of formula (1). The compound of formula (1) may be purifiedby any suitable methods known in the art such as chromatography onsilica gel, trituration, precipitation or crystallization.

Step 2—Preparation of a Compound of Formula (2)

The compounds of formula (2) can be made by combining compounds (1) and(C). Compound (C) is commercially available or can be made by methodsknown in the art. With respect to compound (C), (R¹)_(n) and (R⁵)_(s) isas defined herein. Compounds (1) and (C) can be mixed in the presence ofa catalyst such as palladium(II) acetate, a phosphine ligand such asdicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine, and abase such as potassium phosphate in a neutral solvent such as toluene.The reaction is carried out at a temperature between 70 and 120° C. forbetween 4 and 72 hours or until the reaction is complete. Uponcompletion, the solvent is removed under reduced pressure and thecompound of formula (2) may be purified by any suitable methods known inthe art such as chromatography on silica gel, trituration, precipitationor crystallization.

Step 3—Preparation of a Compound of Formula (3)

The compounds of formula (3) can be made by combining compounds (2) and(D). Compound (D) is commercially available or can be made by methodsknown in the art. With respect to compound (D), R² is as defined herein.Compounds (2) and (D) can be mixed in the presence of a reducing agentsuch as sodium dithionite in a solvent such as a mixture ofdimethylsulfoxide and ethanol. The reaction is carried out at atemperature between 30 and 120° C. for between 4 and 72 hours or untilthe reaction is complete. The reaction mixture is then partitionedbetween water and an organic solvent such as ethyl acetate or methylenechloride, followed by washing with water and brine. The organic phasecan be concentrated to obtain the compound of formula (3). The compoundof formula (3) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation orcrystallization.

Step 4—Preparation of a Compound of Formula (4)

The compounds of formula (4) may be prepared by hydrolysis of thecompounds of formula (3) by standard methods. A compound of formula (3)is dissolved or slurried in a solvent such as tetrahydrofuran or dioxaneand lithium hydroxide may be added either as a solution in water or withsome water. The reaction is carried out at ambient temperature forbetween 1 and 24 hours or until the reaction is complete. The reactionis then acidified with an acid such as hydrochloric acid and the solventis removed under reduced pressure to give a compound of formula (4).

Step 5—Preparation of a Compound of Formula (5)

The compounds of formula (5) may be prepared by amidation of thecompounds of formula (4) by standard methods. A compound of formula (4)may be reacted with ammonium chloride in the presence ofhydroxybenzotriazole (HOBt), a base such as triethylamine ordiisopropylethylamine, andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) in asolvent such as dimethylformamide. The reaction is carried out at atemperature between ambient temperature and 60° C. for between 2 and 96hours or until the reaction is complete. To extract the compound offormula (5), an organic solvent such as ethyl acetate may be added,followed by washing with water and brine. The organic phase can beconcentrated under reduced pressure to obtain the compound of formula(5). Alternatively, the compound of formula (5) may precipitate with theaddition of water and may be recovered by filtration. The compound offormula (5) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, preparative HPLC, trituration,precipitation or crystallization.

Step 6—Preparation of a Compound of Formula (IM)

The compounds of formula (IM) can be made from the compounds of formula(5) by a two-step procedure. A compound of formula (5) may be reactedwith a large excess of an appropriate reagent such as1,1-dimethoxy-N,N-dimethylethanamine or1,1-dimethoxy-N,N-dimethylmethanamine at a temperature between ambienttemperature and 140° C. for between 0.5 and 24 hours or until thereaction is complete. The reagent is removed under reduced pressure andthe residue can be dissolved in acetic acid followed by addition ofhydrazine. The reaction is stirred at a temperature between ambienttemperature and 100° C. for between 0.5 and 24 hours or until thereaction is complete. The solvent is removed under reduced pressure andthe compound of formula (IM) can be dissolved in an organic solvent suchas ethyl acetate, followed by washing with a solution of saturatedsodium bicarbonate and brine. The organic phase is concentrated underreduced pressure to obtain the compound of formula (IM). The compound offormula (IM) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, preparative HPLC, trituration,precipitation or crystallization.

If protecting groups are present on the compound of formula (IM) at thispoint, they may be removed by appropriate methods. For example, Boc orTHP groups may be removed by treatment with an acid such astrifluoroacetic acid in a solvent such as methylene chloride. Thecompound of formula (IM) may be purified by any suitable methods knownin the art such as chromatography on silica gel, preparative HPLC,trituration, precipitation or crystallization.

If the compound of formula (IM) is a mixture of atropisomers, theisomers may be separated using a chiral chromatography method. Thesolvents and chromatography column used will depend on the specificcompound being separated, but normal phase, reverse phase orsupercritical fluid chromatography may be used.

Alternatively, compounds of formula (IM) can be made as shown inReaction Scheme 2.

Step 1—Preparation of a Compound of Formula (6)

The compounds of formula (6) can be made by combining ethyl3-amino-2-nitrobenzoate with the compounds (C). Ethyl3-amino-2-nitrobenzoate is commercially available or can be made bymethods known in the art. Compound (C) is commercially available or canbe made by methods known in the art. With respect to compound (C),(R¹)_(n) and (R⁵)_(s) is as defined herein. Ethyl3-amino-2-nitrobenzoate and compound (C) can be mixed in the presence ofa base such as cesium carbonate in a suitable solvent such asdimethylformamide. After further stirring at a temperature between 70and 130° C. for between 2 and 48 hours, the reaction mixture is allowedto cool to room temperature. To extract the compound of formula (6), anorganic solvent such as ethyl acetate may be added, followed by washingwith water and brine. The organic phase can be concentrated underreduced pressure to obtain the compound of formula (6). The compound offormula (6) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation orcrystallization.

Step 2—Preparation of a Compound of Formula (7)

The compounds of formula (7) can be made by reduction of the nitro groupof the compounds of formula (6) using standard methods. A reducing agentsuch as zinc dust can be added to a solution of a compound of formula(6) in a suitable solvent such as acetic acid. After further stirring atambient temperature for between 0.5 and 24 hours, the reaction mixturecan be filtered and the solvent can be removed under reduced pressure.The compound of formula (7) can be dissolved in an organic solvent suchas ethyl acetate and washed with a solution of sodium bicarbonate, waterand brine. The organic phase can be concentrated under reduced pressureto obtain the compound of formula (7). The compound of formula (7) maybe purified by any suitable methods known in the art such aschromatography on silica gel, trituration, precipitation orcrystallization.

Step 3—Preparation of a Compound of Formula (8)

The compounds of formula (8) can be made by bromination of the compounds(7) using standard methods. A brominating agent such as bromine can beadded to a solution of a compound of formula (7) in a suitable solventsuch as dichloromethane. After further stirring at a temperature between0 and 40° C. for between 0.5 and 24 hours, the reaction mixture can bequenched with a reducing agent such as sodium thiosulfate. The mixturecan then be diluted with an organic solvent such as ethyl acetate andwashed with a solution of sodium carbonate, water and brine. The organicphase can be concentrated under reduced pressure to obtain the compoundof formula (8). The compound of formula (8) may be purified by anysuitable methods known in the art such as chromatography on silica gel,trituration, precipitation or crystallization.

Step 4—Preparation of a Compound of Formula (9)

The compounds of formula (9) can be made by combining the compounds (8)with an acid anhydride (E). Compound (E) is commercially available orcan be made by methods known in the art. With respect to compound (E),R² is as defined herein. A solution of a compound of formula (8) and anexcess of an acid anhydride (E) in a solvent such as acetic acid can bestirred at a temperature between 80 and 140° C. for between 1 and 24hours. The solvent can then be removed under reduced. The compound offormula (9) can be dissolved in an organic solvent such as ethyl acetateand washed with a solution of sodium bicarbonate, water and brine. Theorganic phase can be concentrated under reduced pressure to obtain thecompound of formula (9). The compound of formula (9) may be purified byany suitable methods known in the art such as chromatography on silicagel, trituration, precipitation or crystallization.

Step 5—Preparation of a Compound of Formula (10)

The compounds of formula (10) can be made by combining the compounds (9)with bis(neopentyl glycolato)diboron. A compound of formula (9) andbis(neopentyl glycolato)diboron can be mixed in the presence of acatalyst such as[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (complexwith dichloromethane) and a base such as potassium acetate in a suitablesolvent such as dioxane. After further stirring at a temperature between70 and 120° C. for between 1 and 48 hours, the reaction mixture isallowed to cool to room temperature. After filtration and concentrationunder reduced pressure, the compound of formula (10) may be purified byany suitable methods known in the art such as chromatography on silicagel, trituration, precipitation or crystallization.

Step 6—Preparation of a Compound of Formula (11)

The compounds of formula (11) can be made by combining compounds (10)and (B). Compound (B) is commercially available or can be made bymethods known in the art. With respect to compound (B), X⁶, X⁷, and R¹⁰³are as defined herein and Y² is Br or I. Compounds (10) and (B) can bemixed in the presence of a catalyst such astetrakis(triphenylphosphine)palladium(0) and a base such as potassiumphosphate tribasic in a suitable solvent such as a mixture of dioxaneand water. After further stirring at a temperature between 70 and 110°C. for between 1 and 24 hours, the reaction mixture is allowed to coolto room temperature. To extract the compound of formula (11), an organicsolvent such as ethyl acetate may be added, followed by washing withwater and brine. The organic phase can be concentrated under reducedpressure to obtain the compound of formula (11). The compound of formula(11) may be purified by any suitable methods known in the art such aschromatography on silica gel, trituration, precipitation orcrystallization.

Step 7—Preparation of a Compound of Formula (4) from a Compound ofFormula (11)

The compounds of formula (4) may be prepared by hydrolysis of thecompounds of formula (11) by standard methods. A compound of formula(11) is dissolved or slurred in a solvent such as tetrahydrofuran ordioxane and lithium hydroxide may be added either as a solution in wateror with some water. The reaction is carried out at ambient temperaturefor between 1 and 24 hours or until the reaction is complete. Thereaction is then acidified with an acid such as hydrochloric acid andthe solvent is removed under reduced pressure to give a compound offormula (4).

Alternatively, compounds of formula (IM) can be made as shown inReaction Scheme 3.

Step 1—Preparation of a Compound of Formula (12)

The compounds of formula (12) can be made by combining the compounds (8)and (F). Compound (8) is made as described is Reaction Scheme 2.Compound (F) is commercially available or can be made by methods knownin the art. With respect to compound (F), R² is as defined herein. Asolution of compound (8) in an excess of compound (F) can be stirred ata temperature between 60 and 140° C. for between 1 and 48 hours. Thesolvent can then be removed under reduced pressure. The compound offormula (12) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation orcrystallization.

Step 2—Preparation of a Compound of Formula (13)

The compounds of formula (13) may be prepared by hydrolysis of thecompounds of formula (12) by standard methods. A compound of formula(12) is dissolved or slurred in a solvent such as tetrahydrofuran ordioxane and lithium hydroxide may be added either as a solution in wateror with some water. The reaction is carried out at ambient temperaturefor between 1 and 24 hours or until the reaction is complete. Thereaction is then acidified with an acid such as hydrochloric acid andthe solvent is removed under reduced pressure to give a compound offormula (13).

Step 3—Preparation of a Compound of Formula (14)

The compounds of formula (14) may be prepared by amidation of thecompounds of formula (13) by standard methods. A compound of formula(13) may be reacted with ammonium chloride in the presence ofhydroxybenzotriazole (HOBt), a base such as triethylamine ordiisopropylethylamine, andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) in asolvent such as dimethylformamide. The reaction is carried out at atemperature between ambient temperature and 60° C. for between 12 and 96hours or until the reaction is complete. To extract the compound offormula (14), an organic solvent such as ethyl acetate may be added,followed by washing with water and brine. The organic phase can beconcentrated under reduced pressure to obtain the compound of formula(14). Alternatively, the compound of formula (14) may precipitate withthe addition of water. The compound of formula (14) may be purified byany suitable methods known in the art such as chromatography on silicagel, trituration, precipitation or crystallization.

Step 4—Preparation of a Compound of Formula (15)

The compounds of formula (15) can be made by combining the compounds(14) and bis(neopentyl glycolato)diboron. A compound of formula (14) andbis(neopentyl glycolato)diboron can be mixed in the presence of acatalyst such as[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (complexwith dichloromethane) and a base such as potassium acetate in a suitablesolvent such as dioxane. After further stirring at a temperature between70 and 120° C. for between 5 and 48 hours, the reaction mixture isallowed to cool to room temperature. If the compound of formula (15)precipitate upon cooling, the material can be recovered by filtration,washing with water and drying under vacuum. Alternatively, to extractthe compound of formula (15), an organic solvent such as ethyl acetatemay be added, followed by washing with water and brine. The organicphase can be concentrated under reduced pressure to obtain the compoundof formula (15). The compound of formula (15) may be purified by anysuitable methods known in the art such as chromatography on silica gel,trituration, precipitation or crystallization.

Step 5—Preparation of a Compound of Formula (5) from a Compound ofFormula (15)

The compounds of formula (5) can be made by combining compounds (15) and(B). Compound (B) is commercially available or can be made by methodsknown in the art. With respect to compound (B), X⁶, X⁷, R³⁰ and R³¹ areas defined herein and Y² is Br or I. Compounds (15) and (B) can be mixedin the presence of a catalyst suchtetrakis(triphenylphosphine)palladium(0) and a base such as potassiumphosphate tribasic in a suitable solvent such as a mixture of dioxaneand water. After further stirring at a temperature between 70 and 110°C. for between 1 and 24 hours, the reaction mixture is allowed to coolto room temperature. To extract the compound of formula (5), an organicsolvent such as ethyl acetate may be added, followed by washing withwater and brine. The organic phase can be concentrated under reducedpressure to obtain the compound of formula (5). The compound of formula(5) may be purified by any suitable methods known in the art such aschromatography on silica gel, preparative HPLC, trituration,precipitation or crystallization.

Preparation of the Compounds of Formula (4) According to Reaction Scheme1 A. Preparation of Methyl 3-amino-2-nitro-5-(pyridin-4-yl)benzoate

Tetrakis(triphenylphosphine)palladium(0) (2.50 g, 2.17 mmol) was addedto a solution of methyl 3-amino-5-chloro-2-nitrobenzoate (5.0 g, 21.7mmol), pyridin-4-ylboronic acid (2.7 g, 21.7 mmol), and potassiumphosphate tribasic (13.8 g, 65 mmol) in THF (200 mL) and water (50 mL).Nitrogen was bubbled for 10 minutes, the vessel was sealed, and thereaction mixture was stirred at 90° C. for 16 hours. Upon cooling, thereaction mixture was partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried with magnesium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography eluting with 5 to 100% of(5% methanol in ethyl acetate) in hexane to afford methyl3-amino-2-nitro-5-(pyridin-4-yl)benzoate.

B. Preparation of Methyl3-amino-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate

Palladium(II) acetate (0.49 g, 2.17 mmol) was added to a solution ofmethyl 3-amino-5-chloro-2-nitrobenzoate (10 g, 43.4 mmol), bis(neopentylglycolato)diboron (19.6 g, 86.7 mmol),1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium chloride (1.8 g, 4.3mmol), and potassium acetate (10.6 g, 108 mmol) in THF (400 mL).Nitrogen was bubbled for 10 minutes, the flask was closed with a septum,and the reaction mixture was stirred at 50° C. for 72 hours. Thereaction mixture was cooled to ambient temperature and the solid wasfiltered. The filtrate was dry loaded onto silica gel and purified bysilica gel column chromatography eluting with 5 to 70% ethyl acetate inhexane to afford methyl3-amino-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrobenzoate. ES/MSm/z=263.2 (ArB(OH)₂+Na)⁺.

Tetrakis(triphenylphosphine)palladium(0) (1.91 mg, 1.66 mmol) was addedto a solution of methyl3-amino-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrobenzoate (6.1 g,19.9 mmol), 2,3-difluoro-4-iodopyridine (4.0 g, 16.6 mmol), andpotassium phosphate tribasic (10.6 g, 49.8 mmol) in dioxane (80 mL) andwater (20 mL). Nitrogen was bubbled for 10 minutes and the reactionmixture was stirred at 80° C. for 10 hours. Upon cooling, the reactionmixture was partitioned between ethyl acetate and water. The organicphase was washed with brine, dried with magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography eluting with 5 to 70% of (5% methanolin ethyl acetate) in hexane to afford methyl3-amino-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate. ES/MS m/z=310.2(M+H)⁺.

The following compounds were prepared using a similar procedure:

-   methyl 3-amino-5-(3-fluoropyridin-4-yl)-2-nitrobenzoate-   methyl 3-amino-5-(2-methylpyridin-4-yl)-2-nitrobenzoate-   methyl 3-amino-5-(2,5-difluoropyridin-4-yl)-2-nitrobenzoate-   methyl    3-amino-5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-nitrobenzoate-   methyl    3-amino-5-(2-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2-nitrobenzoate-   methyl    3-amino-5-(2,6-bis((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2-nitrobenzoate-   methyl    3-amino-5-(6-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2-nitrobenzoate-   methyl    3-amino-2-nitro-5-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)benzoate-   methyl 3-amino-5-(2,5-difluoropyridin-4-yl)-2-nitrobenzoate

C. Preparation of Methyl3-((8-chloroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate

To a solution of 4,8-dichloroquinoline (384 mg, 1.94 mmol) and methyl3-amino-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate (500 mg, 1.62 mmol)in toluene (8.0 mL) was added XPhos (185 mg, 0.39 mmol), palladiumacetate (29 mg, 0.13 mmol) and potassium phosphate tribasic (686 mg,3.23 mmol). Nitrogen was bubbled for 5 min. The vessel was closed andthe reaction mixture was stirred at 100° C. for overnight. Upon cooling,the reaction mixture was filtered. The filtrate was dry loaded ontosilica gel and purified using silica gel chromatography eluting with 5to 100% of (10% methanol in ethyl acetate) in hexane to afford methyl3-((8-chloroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate.ES/MS m/z=471.1 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   methyl    3-((8-chloroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((5,8-difluoroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((5,8-dichloroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((5-fluoroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((5-methylquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((8-chloro-2-methylquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((2-methylquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((8-chloro-5-fluoroquinolin-4-yl)amino)-2-nitro-5-(pyridin-4-yl)benzoate-   methyl    3-((8-chloroquinolin-4-yl)amino)-5-(3-fluoropyridin-4-yl)-2-nitrobenzoate-   methyl    3-((8-chloroquinolin-4-yl)amino)-5-(2-methylpyridin-4-yl)-2-nitrobenzoate-   methyl    5-(2,5-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2,3-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((8-chloro-5-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((7-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((5-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2,6-bis((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(6-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    3-((8-chloroquinolin-4-yl)amino)-2-nitro-5-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)benzoate-   methyl    5-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((8-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2,3-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    3-((8-chloro-5-fluoroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate-   methyl    5-(2,3-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2,5-difluoropyridin-4-yl)-3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    5-(2,3-difluoropyridin-4-yl)-3-((8-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    3-((8-chloro-3-methylquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate-   methyl    3-((3-chloro-8-fluoroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate-   methyl    5-(2,3-difluoropyridin-4-yl)-3-((5-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   methyl    3-((5-chloro-8-fluoroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate

D. Preparation of a Methyl1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate

Acetaldehyde (0.15 mL, 2.74 mmol) was added to a solution of methyl3-((8-chloroquinolin-4-yl)amino)-5-(2,3-difluoropyridin-4-yl)-2-nitrobenzoate(215 mg, 0.46 mmol) and sodium dithionite (281 mg, 1.37 mmol) in ethanol(2.5 mL) and DMSO (2.5 mL). The reaction vessel was closed and thereaction mixture was stirred at 80° C. for overnight. Upon cooling, thereaction mixture was partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried with magnesium sulfate,filtered, and concentrated under reduced pressure to afford methyl1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate.ES/MS m/z=465.2 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   methyl    1-(8-chloroquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    2-methyl-1-(5-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloro-2-methylquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    2-methyl-1-(2-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloroquinolin-4-yl)-2-(oxetan-3-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloroquinolin-4-yl)-6-(3-fluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(7-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(7-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,6-bis((di-tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloroquinolin-4-yl)-2-methyl-6-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-isopropyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-2-(cyclopropylmethyl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2-((di-tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(8-chloro-3-methylquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(3-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazole-4-carboxylate-   methyl    2-(cyclopropylmethyl)-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate

E. Preparation of1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicAcid

Aqueous 1M lithium hydroxide (1.0 mL) was added to a solution of methyl1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate(206 mg, 0.44 mmol) in THF (4 mL). The reaction was stirred at ambienttemperature for 1 hour. The reaction mixture was acidified with 4N HClin dioxane. The resulting solution was concentrated to afford1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicacid which was used without further purification for the next step.ES/MS m/z 451.10 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   1-(8-chloroquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   2-methyl-1-(5-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloro-2-methylquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   2-methyl-1-(2-methylquinolin-4-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloroquinolin-4-yl)-2-(oxetan-3-yl)-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloroquinolin-4-yl)-6-(3-fluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(7-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(7-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,6-bis((tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-isopropyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-cyclopropyl-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-(cyclopropylmethyl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid-   2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloro-3-methylquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(3-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazole-4-carboxylic    acid-   2-(cyclopropylmethyl)-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid

Example Name MS NMR 1 1-(8-chloroquinolin- 415.1 1H NMR (400 MHz,DMSO-d6) 4-yl)-2-methyl-6- δ 9.33 (d, J = 4.5 Hz, 1H), 8.65 pyridin-4-(d, J = 5.5 Hz, 3H), 8.32 (s, ylbenzimidazole-4- 1H), 8.10 (dd, J = 7.5,1.2 Hz, carboxylic acid 1H), 8.03 (d, J = 4.5 Hz, 1H), 7.96 (s, 3H),7.87 (s, 1H), 7.57 (dd, J = 8.4, 7.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H),2.46 (s, 3H).

F. Preparation of6-(2-aminopyrimidin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide

6-(2-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicacid (17 mg, 0.032 mmol) was dissolved in dichloromethane (1.0 mL) andtrifluoroacetic acid (50 μL, 0.64 mmol) was added. The reaction mixturewas stirred at ambient temperature for 1 hour, after which the reactionwas concentrated under reduced pressure. The resultant was purified byHPLC eluting with 5-95% water/acetonitrile (0.1% v/v trifluoroaceticacid). The appropriate fractions were pooled and lyophilized to afford6-(2-aminopyridimin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamideas a 2,2,2-trifluoroacetic acid salt (Example 2).

Example Name MS NMR 2 6-(2-amino- 431.1 1H NMR (400 MHz, DMSO-d6)pyrimidin- δ 9.37-9.33 (m, 1H), 8.72 (d, 4-yl)-1-(8- J = 1.6 Hz, 1H),8.22 (dd, chloro- J = 5.5, 0.5 Hz, 1H), 8.11 (dd, quinolin-4-yl)- J =7.5, 1.2 Hz, 1H), 8.05 (d, 2-methyl- J = 4.5 Hz, 1H), 7.97 (d, J =benzimidazole- 1.7 Hz, 1H), 7.63-7.55 (m, 1H), 4-carboxylic acid 7.35(d, J = 8.4 Hz, 1H), 7.21 (d, J = 5.6 Hz, 1H), 7.06 (s, 2H), 2.46 (s,3H). 3 1-(8-chloroquinolin- 456.1 1H NMR (400 MHz, DMSO-d6)4-yl)-2-methyl-6- δ 9.63 (s, 1H), 9.38 (d, J = (9H-purin-6- 4.5 Hz, 1H),8.82 (s, 1H), 8.61 yl)benzimidazole-4- (s, 1H), 8.56 (s, 1H), 8.16-8.11carboxylic acid (m, 2H), 7.61 (dd, J = 8.5, 7.5 Hz, 1H), 7.45 (d, J =8.5 Hz, 1H), 2.51 (s, 3H).

G. Preparation of6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic

Ammonium hydroxide (28-30% solution in water, 0.75 mL) was added to asolution of crude6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicacid (0.17 mmol) in DMSO (2.0 mL). The reaction vessel was sealed andthe reaction mixture was stirred at 100° C. overnight. The excessammonia was removed under reduced pressure and the resulting solutionwas purified by HPLC eluting with 5-95% water/acetonitrile (0.1% v/vtrifluoroacetic acid). The appropriate fractions were pooled andlyophilized to afford6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicacid as a 2,2,2-trifluoroacetic acid salt (Example 4).

Example Name MS NMR 4 6-(2-amino-3- 450.1 1H NMR (400 MHz, DMSO-d6)fluoro- δ 9.31(d, J = 4.5 Hz, 1H), 8.12 pyridin-4-yl)-1- (t, J = 1.5 Hz,1H), 8.07 (d, (5,8-difluoro- J = 4.5 Hz, 1H), 7.78 (ddd, J = quinolin-4-10.0, 8.8, 4.3 Hz, 1H), 7.73 (d, yl)-2-methyl- J = 6.0 Hz, 1H), 7.71 (s,1H), benzimidazole- 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 4-carboxylic acid1H), 6.82 (t, J = 5.8 Hz, 1H), 2.49 (s, 3H).

Preparation of the Compounds of Formula (4) According to Reaction Scheme2 A. Preparation of tert-butyl4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate

A suspension of 2,4-dichloroquinoline (6.4 g, 32.2 mmol), tert-butylpiperazine-1-carboxylate (5.0 g, 26.8 mmol) and diethylisopropylamine(6.5 mL, 38.0 mmol) was stirred in a sealed at 100° C. for 2 days. Uponcooling, the reaction mixture was concentrated in vacuuo to affordmaterial which was purified by column chromatography on SiO2 elutingwith EtOAc in hexanes (0-15%) to afford tert-butyl4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate (3.2 g, 34%). ES/MSm/z=348.1 (M+H)+.

B. Preparation of 4-chloro-2-(1-trityl-1H-pyrazol-4-yl)quinoline

A sealed tube was charged with 2,4-dichloroquinoline (1.0 g, 5.05 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole(2.2 g, 5.05 mmol), K₃PO₄ (3.2 g, 15.1 mmol) and Pd(PPh₃)₄ (0.58 g, 0.50mmol) followed by dioxane (50 mL) and water (12 mL). The reactionmixture was stirred at 90° C. for 3 h. Upon cooling, the reactionmixture was absorbed on SiO2 followed by purification on columnchromatography on SiO2 eluting with EtOAc in hexanes (0-100%) to afford4-chloro-2-(1-trityl-1H-pyrazol-4-yl)quinoline (1.15 g, 48%). ES/MSm/z=472.2 (M+H)+.

C. Preparation of ethyl3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate

To a cooled solution of 4-chloro-5,8-difluoroquinoline (171 g, 859.3mmol) in DMF (1.7 L) were added ethyl 3-amino-2-nitrobenzoate (181.5 g,859.3 mmol) and Cs₂CO₃ (614.4 g, 1890 mmol). The reaction mixture wasstirred at 90° C. for 18 hours. The reaction mixture was cooled down andfiltered through a pad of Celite. The filtrate was partitioned betweenethyl acetate and water. The organic phase was washed with brine, driedwith sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by silica gel column chromatographyeluting with 30% ethyl acetate in petroleum ether to afford ethyl3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate. ES/MS m/z=374.4(M+H)⁺.

The following compounds were prepared using a similar procedure:

-   ethyl 3-((5,8-dichloroquinolin-4-yl)amino)-2-nitrobenzoate-   ethyl 3-((5-chloroquinolin-4-yl)amino)-2-nitrobenzoate-   ethyl 3-((5-chloro-8-fluoroquinolin-4-yl)amino)-2-nitrobenzoate

D. Preparation of ethyl 3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate

Palladium (II) acetate (103 mg, 0.46 mmol) was added to a mixture ofethyl 3-amino-2-nitrobenzoate (1.2 g, 5.7 mmol), 4,8-dichloroquinoline(1.24 g, 6.3 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (653mg, 1.37 mmol), and potassium phosphate (2.42 g, 11.4 mmol) in toluene(23 mL). The resultant was degassed and stirred at 90° C. for 16 hours.The reaction mixture was cooled to room temperature and dry loaded ontosilica gel and purified eluting with 0 to 100% ethyl acetate in hexanesto afford the title compound as a brown solid. ES/MS m/z=372.1 (M+H)⁺.The following compounds were prepared using a similar procedure:

-   ethyl 3-((5,7-difluoroquinolin-4-yl)amino)-2-nitrobenzoate-   ethyl 3-((8-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   ethyl 3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate-   ethyl 3-((5-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   ethyl 3-((8-chloro-5-fluoroquinolin-4-yl)amino)-2-nitrobenzoate-   tert-butyl    4-(4-((3-(ethoxycarbonyl)-2-nitrophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate-   ethyl    2-nitro-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzoate-   tert-butyl    4-(4-((2-nitrophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate

E. Preparation of a Compound of Formula (7) in which n=2,(R¹)_(n)=5,8-difluoro

To a solution of ethyl3-((5,8-difluoroquinolin-4-yl)amino)-2-nitrobenzoate (158 g, 423.49mmol) in AcOH (1.3 L) and MeOH (320 mL) at 0° C., Zn-dust (166.1 g, 2541mmol) was slowly added and the mixture was stirred at ambienttemperature for 1 hour. The reaction mixture was filtered through a padof Celite and evaporated under reduced pressure. The resulting residuewas suspended in DCM and washed with an aqueous saturated solution ofNaHCO₃ followed brine. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to give ethyl2-amino-3-((5,8-difluoroquinolin-4-yl)amino)benzoate. ES/MS m/z=344.0(M+H)⁺.

The following compounds were prepared using a similar procedure:

-   ethyl 2-amino-3-((5,7-difluoroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-3-((5,8-dichloroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-3-((5-chloro-8-fluoroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-3-((5-chloroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-3-((8-fluoroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-3-((8-chloroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-3-((5-fluoroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-3-((8-chloro-5-fluoroquinolin-4-yl)amino)benzoate-   tert-butyl    4-(4-((2-amino-3-(ethoxycarbonyl)phenyl)amino)quinolin-2-yl)piperazine-1-carboxylate-   ethyl    2-amino-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzoate-   tert-butyl    4-(4-((2-aminophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate

F. Preparation of Ethyl2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate

To a stirred solution of ethyl2-amino-3-((5,8-difluoroquinolin-4-yl)amino)benzoate (135 g, 393 mmol)in DCM (2.7 L) at 0° C., bromine (30.4 mL, 1180 mmol) was added and themixture was stirred at 0° C. for 1 hour. The reaction mixture wasquenched with aqueous Na₂S₂O₃, diluted with DCM and washed with anaqueous saturated solution of NaHCO₃ followed by brine. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give ethyl2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate. ES/MSm/z=422.0 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   ethyl 2-amino-5-bromo-3-((5,7-difluoroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-5-bromo-3-((5,8-dichloroquinolin-4-yl)amino)benzoate-   ethyl    2-amino-5-bromo-3-((5-chloro-8-fluoroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-5-bromo-3-((5-chloroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-5-bromo-3-((8-fluoroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-5-bromo-3-((8-chloroquinolin-4-yl)amino)benzoate-   ethyl 2-amino-5-bromo-3-((5-fluoroquinolin-4-yl)amino)benzoate-   ethyl    2-amino-5-bromo-3-((8-chloro-5-fluoroquinolin-4-yl)amino)benzoatetert-butyl    4-(4-((2-amino-5-bromo-3-(ethoxycarbonyl)phenyl)amino)quinolin-2-yl)piperazine-1-carboxylateethyl    2-amino-5-bromo-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzoate-   tert-butyl    4-(4-((2-amino-5-bromophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate

G. Preparation of Ethyl6-bromo-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate

A solution of ethyl2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate (103 g, 244mmol) in Ac₂O (515 mL) and AcOH (1 L) was refluxed for 18 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas diluted with ethyl acetate and washed with an aqueous saturatedsolution of NaHCO₃ followed by brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was triturated with petroleum ether to give ethyl

-   6-bromo-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate.    ES/MS m/z=446.2 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   ethyl    6-bromo-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-bromo-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-bromo-1-(5-chloro-8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-bromo-1-(5-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-bromo-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-bromo-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-bromo-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-bromo-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate

H. Preparation of Ethyl6-bromo-1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate

A solution tert-butyl4-(4-((2-amino-5-bromo-3-(ethoxycarbonyl)phenyl)amino)quinolin-2-yl)piperazine-1-carboxylate(2.29 g, 4.0 mmol) in trimethyl orthoformate (30 mL) was refluxed for 30minutes. The reaction mixture was cooled to room temperature and dryloaded onto silica gel and purified eluting with 0 to 100% ethyl acetatein hexanes to afford the title compound as a brown solid. ES/MSm/z=580.1 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   ethyl    6-bromo-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   tert-butyl    4-(4-(6-bromo-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate

I. Preparation of Ethyl1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (2.74 g, 3.36 mmol) was added to a solution of ethyl6-bromo-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate(10 g, 22.4 mmol), bis(neopentyl glycolato)diboron (7.6 g, 33.6 mmol)and potassium acetate (5.5 g, 56.0 mmol) in dioxane (100 mL). Nitrogenwas bubbled for 10 minutes and the reaction mixture was stirred atrefluxing temperature for 24 hours. The reaction mixture was cooled toambient temperature and the solid was filtered. The filtrate was dryloaded onto silica gel and purified by silica gel column chromatographyeluting with 25 to 100% ethyl acetate in hexane to afford ethyl1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate.ES/MS m/z=412.2 (ArB(OH)₂+H)⁺.

The following compounds were prepared using a similar procedure:

-   ethyl    1-(5,7-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-dichloroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5-chloro-8-fluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5-chloroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(8-chloroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(8-chloro-5-fluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   tert-butyl    4-(4-(6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate

J. Preparation of Ethyl6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (241 mg, 0.21 mmol) was addedto a solution of ethyl1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate(1.0 g, 2.09 mmol), 4-bromo-2-(difluoromethyl)pyridine (521 mg, 2.5mmol), and potassium phosphate tribasic (1.11 g, 5.22 mmol) in dioxane(10 mL) and water (3 mL). Nitrogen was bubbled for 10 minutes and thereaction mixture was stirred at 90° C. for 4 hours. Upon cooling, thereaction mixture was partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried with magnesium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography eluting with 5 to 100% of(20% methanol in ethyl acetate) in hexane to afford ethyl6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate.ES/MS m/z=495.2 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   ethyl    6-(2-cyanopyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-6-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(3-chloro-2-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2,3,5-trifluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2-cyanopyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2-cyanopyridin-4-yl)-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(8-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2-cyanopyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2-cyanopyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyrimidin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(6-methylpyrimidin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(6-amino-5-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2-chloropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2,3-difluoropyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   ethyl    1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2-cyanopyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   ethyl    6-(2-cyanopyridin-4-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate-   tert-butyl    4-(4-(6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate

K. Preparation of6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicAcid

Aqueous 1M lithium hydroxide (3.4 mL) was added to ethyl6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylate(847 mg, 1.71 mmol) in THF (10 mL). The reaction was stirred at ambienttemperature for overnight. The reaction mixture was acidified with 4NHCl in dioxane. The resulting solution was concentrated under reducedpressure to afford6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicacid which was used without further purification for the next step.ES/MS m/z 467.20 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   6-(2-cyanopyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-6-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(3-chloro-2-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2,3,5-trifluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-cyanopyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-cyanopyridin-4-yl)-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-cyanopyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-cyanopyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyrimidin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(6-methylpyrimidin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(6-amino-5-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-chloropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2,3-difluoropyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-(2-cyanopyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid-   6-(2-cyanopyridin-4-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid

Preparation of the Compounds of Formula (5) According to Reaction Scheme1 A. Preparation of6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide

To a solution of6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylicacid (797 mg, 1.71 mmol) in DMF (8.0 mL) were added ammonium chloride(640, 12.0 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (1.31 g, 6.84 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (1.31 g, 6.84 mmol) and diethylisopropylamine (2.98 mL,17.1 mmol). The mixture was stirred at 50° C. for overnight. Thematerial was precipitated with the addition of water. The resultingsolid was filtered, washed with water, and dried under high vacuum forovernight to afford6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide.ES/MS m/z 466.2 (M+H)⁺.

The following compounds were prepared using a similar procedure:

-   1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   tert-butyl    (4-(4-carbamoyl-2-ethyl-1-(7-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(7-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(8-chloro-5-fluoroquinolin-4-yl)-2-(oxetan-3-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-2-cyclopropyl-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   tert-butyl    (4-(4-carbamoyl-2-(cyclopropylmethyl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   tert-butyl    (4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,5-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   2-cyclopropyl-6-(2,3-difluoropyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   1-(8-chloro-3-methylquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-6-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(3-chloro-2-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2,3,5-trifluoropyridin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoro-3-methylpyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(3-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-2-ethyl-1-(5-fluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazole-4-carboxamide-   2-(cyclopropylmethyl)-6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(5-chloro-8-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(5-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2-cyanopyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2-cyanopyridin-4-yl)-1-(5,8-dichloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(8-chloroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2-cyanopyridin-4-yl)-1-(5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2-cyanopyridin-4-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-(2-cyanopyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2-cyanopyrimidin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-(2-methylpyrimidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide1-(5,8-difluoroq-   uinolin-4-yl)-2-methyl-6-(6-methylpyrimidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide-   1-(5,8-difluoroquinolin-4-yl)-6-(2-fluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2-chloropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   6-(2,3-difluoropyridin-4-yl)-1-(5,7-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide-   tert-butyl    4-(4-(4-carbamoyl-6-(2,3-difluoropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate-   tert-butyl    4-(4-(4-carbamoyl-6-(2-cyanopyridin-4-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate-   6-(2-cyanopyridin-4-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide

Compounds may be referred to by Example number with reference to thebelow tables.

Example Name MS NMR 5 1-(8-chloroquinolin- 400.0 1H NMR (400 MHz,DMSO-d6) 4-yl)-6-pyridin-4- δ 9.30 (dd, J = 4.5, 0.6 Hz, 1H),ylbenzimidazole-4- 9.08 (d, J = 3.0 Hz, 1H), 9.06 (d, J = 0.6 Hz,carboxamide 1H), 8.76-8.70 (m, 2H), 8.47 (dd, J = 1.8, 0.6 Hz, 1H),8.14-8.05 (m, 6H), 7.65-7.58 (m, 1H), 7.57-7.52 (m, 1H). 6 1-(5,8- 416.11H NMR (400 MHz, DMSO-d6) difluoroquinolin-4- δ 9.32 (d, J = 4.5 Hz,1H), yl)-2-methyl-6- 9.10 (d, J = 3.0 Hz, 1H), pyridin-4- 8.74-8.67 (m,2H), 8.41 (dd, J = 1.8, 0.6 Hz, ylbenzimidazole-4- 1H), 8.12-8.03 (m,4H), carboxamide 7.94 (dd, J = 1.9, 0.6 Hz, 1H), 7.78 (td, J = 9.6, 4.2Hz, 1H), 7.45 (ddd, J = 12.2, 8.7, 3.7 Hz, 1H), 2.46 (s, 3H). 71-(8-chloro-2- 428.1 1H NMR (400 MHz, DMSO-d6) methylquinolin-4-yl)- δ9.13 (d, J = 3.1 Hz, 1H), 2-methyl-6-pyridin- 8.68 (d, J = 5.9 Hz, 2H),8.41 (d, J = 1.8 Hz, 4-ylbenzimidazole-4- 1H), 8.07 (s, 1H), carboxamide8.10-7.98 (m, 3H), 7.93 (s, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.52-7.42 (m,1H), 7.24-7.18 (m, 1H), 2.83 (s, 3H), 2.46 (d, J = 0.6 Hz, 3H). 81-(5-fluoroquinolin- 398.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-2-methyl-6- δ9.27 (d, J = 4.5 Hz, 1H), 9.12 (s, pyridin-4- 1H), 8.76-8.71 (m, 2H),8.42 (d, ylbenzimidazole-4- J = 1.8 Hz, 1H), 8.16 (dd, J = 7.5,carboxamide 5.6 Hz, 3H), 8.08 (s, 1H), 7.97-7.93 (m, 2H), 7.45 (dd, J =12.4, 7.8 Hz, 1H), 2.44 (d, J = 0.8 Hz, 3H). 9 2-methyl-1-(5- 394.1 1HNMR (400 MHz, DMSO-d6) methylquinolin-4-yl)- δ 9.16 (dd, J = 4.4, 0.6Hz, 1H), 6-pyridin-4- 9.12 (d, J = 3.0 Hz, 1H), ylbenzimidazole-4-8.76-8.71 (m, 2H), 8.45 (dd, J = 1.9, carboxamide 0.7 Hz, 1H), 8.23-8.18(m, 2H), 8.15 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 3.0 Hz, 1H), 7.86 (dd, J= 1.9, 0.7 Hz, 1H), 7.82-7.76 (m, 2H), 7.47 (d, J = 7.0 Hz, 1H), 2.39(s, 3H), 1.72 (s, 3H). 10 2-methyl-1-(2- 394.2 1H NMR (400 MHz, DMSO-d6)methylquinolin-4-yl)- δ 9.15 (s, 1H), 8.70 (d, J = 5.7 Hz, 6-pyridin-4-2H), 8.42 (d, J = 1.8 Hz, 1H), ylbenzimidazole-4- 8.16 (d, J = 8.4 Hz,1H), 8.07 (d, J = 8.1 Hz, carboxamide 3H), 7.89-7.76 (m, 3H), 7.59-7.45(m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 2.80 (s, 3H), 2.45 (s, 3H). 111-(8-chloro-5- 432.1 1H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- δ9.39 (d, J = 4.5 Hz, 1H), 2-methyl-6-pyridin- 9.10 (d, J = 3.1 Hz, 1H),4-ylbenzimidazole-4- 8.75-8.68 (m, 2H), 8.42 (d, J = 1.8 Hz, 1H),carboxamide 8.15-8.04 (m, 5H), 7.96 (d, J = 1.8 Hz, 1H), 7.46 (dd, J =11.9, 8.5 Hz, 1H), 2.46 (s, 3H). 12 1-(8-chloroquinolin- 456.2 1H NMR(400 MHz, DMSO-d6) 4-yl)-2-(oxetan-3-yl)- δ 9.31 (d, J = 4.4 Hz, 1H),6-pyridin-4- 9.19 (d, J = 3.0 Hz, 1H), ylbenzimidazole-4- 8.79-8.72 (m,3H), 8.50 (d, J = 1.8 Hz, 1H), carboxamide 8.23-8.15 (m, 4H), 8.09 (dd,J = 7.6, 1.2 Hz, 1H), 7.97-7.91 (m, 2H), 7.57-7.51 (m, 1H), 7.26 (dd, J= 8.5, 1.2 Hz, 1H), 5.04 (t, J = 6.2 Hz, 1H), 4.95 (t, J = 6.1 Hz, 1H),4.72 (dd, J = 8.6, 5.6 Hz, 1H), 4.55 (dd, J = 8.5, 5.6 Hz, 1H),4.32-4.21 (m, 1H). 13 1-(8-chloroquinolin- 414.1 1H NMR (400 MHz,DMSO-d6) 4-yl)-2-methyl-6- δ 9.32 (d, J = 4.5 Hz, 1H), pyridin-4- 9.14(d, J = 3.2 Hz, 1H), ylbenzimidazole-4- 8.55-8.50 (m, 2H), 8.31 (d, J =1.8 Hz, 1H), carboxamide 8.09 (dd, J = 7.5, 1.2 Hz, 1H), 8.02 (dd, J =8.3, 3.9 Hz, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.65-7.61 (m, 2H), 7.57 (dd,J = 8.5, 7.5 Hz, 1H), 7.29 (dd, J = 8.5, 1.2 Hz, 1H), 2.44 (s, 3H). 141-(8-chloroquinolin- 432.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-6-(3- δ 9.31(dd, J = 4.5, 0.6 Hz, 1H), fluoropyridin-4-yl)-2- 9.12 (s, 1H), 8.58 (d,J = 2.7 Hz, methylbenzimidazole- 1H), 8.39 (dd, J = 5.1, 0.9 Hz,4-carboxamide 1H), 8.22 (t, J = 1.7 Hz, 1H), 8.09 (dd, J = 7.6, 1.3 Hz,1H), 8.04 (d, J = 4.5 Hz, 2H), 7.63-7.50 (m, 3H), 7.33 (dd, J = 8.4, 1.2Hz, 1H), 2.47 (s, 3H). 15 1-(8-chloroquinolin- 428.1 1H NMR (400 MHz,DMSO-d6) 4-yl)-2-methyl-6-(2- δ 9.35 (dd, J = 4.5, 0.7 Hz, 1H),methylpyridin-4- 9.14 (d, J = 3.2 Hz, 1H), 8.62 (d, J = 6.2 Hz,yl)benzimidazole-4- 1H), 8.46 (s, 1H), carboxamide 8.13-8.08 (m, 3H),8.05 (d, J = 4.5 Hz, 1H), 7.85 (s, 1H), 7.62-7.54 (m, 1H), 7.35-7.27 (m,1H), 2.62 (s, 3H), 2.45 (d, J = 0.8 Hz, 3H). 16 6-(2-cyanopyridin-4-441.1 1H NMR (400 MHz, DMSO-d6) yl)-1-(5,8- δ 9.32 (d, J = 4.5 Hz, 1H),difluoroquinolin-4- 9.10 (d, J = 3.1 Hz, 1H), 8.69 (dd, J = 5.3, yl)-2-0.8 Hz, 1H), 8.38-8.33 (m, methylbenzimidazole- 2H), 8.09-8.01 (m, 3H),7.90 (d, 4-carboxamide J = 1.8 Hz, 1H), 7.82-7.74 (m, 1H), 7.46 (ddd, J= 12.4, 8.7, 3.8 Hz, 1H), 2.44 (s, 3H). 157 6-(6-amino-5- 457.1 1H NMR(400 MHz, DMSO-d6) cyanopyrimidin-4- δ 9.30 (d, J = 4.5 Hz, 1H),yl)-1-(5,8- 9.08 (d, J = 3.1 Hz, 1H), difluoroquinolin-4- 8.52-8.43 (m,2H), 8.05 (dd, J = 23.3, 3.8 Hz, yl)-2-methyl-1H- 2H), 7.83-7.70 (m,2H), benzo[d]imidazole-4- 7.45 (ddd, J = 12.3, 8.8, 3.8 Hz, carboxamide1H), 2.49 (s, 3H).

B. Preparation of6-(2-aminopyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide

tert-Butyl(4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate(50 mg, 0.10 mmol) was dissolved in dichloromethane (1.0 mL) andtrifluoroacetic acid (145 μL, 1.89 mmol) was added. The reaction mixturewas stirred at ambient temperature for 1 hour, after which the reactionwas concentrated under reduced pressure. The resultant was purified byHPLC eluting with 5-95% water/acetonitrile (0.1% v/v trifluoroaceticacid). The appropriate fractions were pooled and lyophilized to afford6-(2-aminopyridin-4-yl)-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamideas a 2,2,2-trifluoroacetic acid salt (Example 23).

Example Name MS NMR 17 6-(2-aminopyridin-4- 431.1 1H NMR (400 MHz,DMSO-d6) yl)-1-(5,8- δ 9.31 (d, J = 4.5 Hz, 1H), 9.09 (s,difluoroquinolin-4- 1H), 8.30 (d, J = 1.8 Hz, 1H), yl)-2- 8.06 (d, J =4.2 Hz, 3H), 7.88 (d, J = 6.8 Hz, methylbenzimidazole- 1H), 7.86-7.73(m, 4-carboxamide 3H), 7.52-7.37 (m, 1H), 7.22 (d, J = 1.4 Hz, 1H),7.20-7.17 (m, 1H), 2.44 (d, J = 1.0 Hz, 3H), 18 6-(2-aminopyridin-4-447.1 1H NMR (400 MHz, DMSO-d6) yl)-1-(8-chloro-5- δ 9.38 (d, J = 4.5Hz, 1H), 9.09 (s, fluoroquinolin-4-yl)- 1H), 8.30 (d, J = 1.9 Hz, 1H),2- 8.12 (dd, J = 8.6, 4.9 Hz, 1H), methylbenzimidazole- 8.08 (d, J = 4.5Hz, 2H), 7.87 (d, J = 6.9 Hz, 4-carboxamide 2H), 7.81 (d, J = 1.9 Hz,1H), 7.47 (dd, J = 11.9, 8.6 Hz, 1H), 7.24 (s, 1H), 7.19 (d, J = 6.9 Hz,1H), 2.44 (s, 3H). 19 6-(2-aminopyrimidin- 430.1 1H NMR (400 MHz,DMSO-d6) 4-yl)-1-(8- δ 9.34 (d, J = 4.5 Hz, 1H), chloroquinolin-4-yl)-9.13 (d, J = 3.1 Hz, 1H), 8.77 (d, J = 1.7 Hz, 2- 1H), 8.22 (d, J = 5.7Hz, methylbenzimidazole- 1H), 8.14-8.08 (m, 1H), 8.06 (d, 4-carboxamideJ = 4.5 Hz, 1H), 8.01 (d, J = 3.1 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H),7.58 (dd, J = 8.4, 7.6 Hz, 1H), 7.30 (dd, J = 8.5, 1.2 Hz, 1H), 7.24 (d,J = 5.8 Hz, 1H), 2.44 (s, 3H). 20 1-(8-chloroquinolin- 455.1 1H NMR (400MHz, DMSO-d6) 4-yl)-2-methyl-6- δ 9.61 (s, 1H), 9.37 (d, J = 4.5 Hz,(9H-purin-6- 1H), 9.17 (d, J = 3.1 Hz, 1H), yl)benzimidazole-4- 8.82 (s,1H), 8.55 (s, 1H), 8.52 (s, carboxamide 1H), 8.15-8.08 (m, 2H), 7.99 (d,J = 3.1 Hz, 1H), 7.59 (dd, J = 8.5, 7.6 Hz, 1H), 7.37 (dd, J = 8.5, 1.2Hz, 1H), 2.47 (s, 3H). 21 6-(6-aminopyrimidin- 430.1 1H NMR (400 MHz,DMSO-d6) 4-yl)-1-(8- δ 9.35 (d, J = 4.5 Hz, 1H), chloroquinolin-4-yl)-9.12 (d, J = 3.1 Hz, 1H), 8.54 (s, 1H), 2- 8.46 (d, J = 1.8 Hz, 1H),8.26 (s, methylbenzimidazole- 3H), 8.15-8.05 (m, 3H), 7.71 (d,4-carboxamide J = 1.8 Hz, 1H), 7.59 (dd, J = 8.5, 7.6 Hz, 1H), 7.31 (dd,J = 8.5, 1.2 Hz, 1H), 6.93 (d, J = 0.8 Hz, 1H), 2.47-2.45 (m, 3H). 221-(8-chloroquinolin- 445.1 1H NMR (400 MHz, DMSO-d6) 4-yl)-6-(2,6- δ11.85 (s, 1H), 9.34 (d, J = 4.5 Hz, diaminopyrimidin-4- 1H), 9.13 (d, J= 3.1 Hz, 1H), yl)-2- 8.30 (s, 1H), 8.17-7.97 (m, 5H),methylbenzimidazole- 7.63-7.59 (m, 1H), 7.58 (d, J = 1.7 Hz,4-carboxamide 1H), 7.30 (dd, J = 8.5, 1.2 Hz, 1H), 6.26 (s, 1H), 2.45(s, 3H). 23 6-(2-aminopyridin-4- 429.1 1H NMR (400 MHz, DMSO-d6)yl)-1-(8- δ 9.33 (d, J = 4.5 Hz, 1H), chloroquinolin-4-yl)- 9.12 (d, J =3.1 Hz, 1H), 8.32 (d, J = 1.8 Hz, 2- 1H), 8.09 (td, J = 7.6, 2.2 Hz,methylbenzimidazole- 2H), 8.04 (d, J = 4.5 Hz, 1H), 4-carboxamide 7.87(d, J = 6.8 Hz, 1H), 7.83 (s, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.58 (dd, J= 8.4, 7.6 Hz, 1H), 7.28 (dd, J = 8.5, 1.2 Hz, 1H), 7.21 (d, J = 1.8 Hz,1H), 7.16 (dd, J = 6.8, 1.9 Hz, 1H), 2.45 (s, 3H).

C. Preparation of6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide

Ammonium hydroxide (28-30% solution in water, 0.75 mL) was added to asolution of6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide(40 mg, 0.09 mmol) in DMSO (2.0 mL). The sealed tube was closed andreaction mixture was stirred at 100° C. for overnight. The excessammonia was removed under reduced pressure and the resulting solutionwas purified by HPLC eluting with 5-95% water/acetonitrile (0.1% v/vtrifluoroacetic acid). The appropriate fractions were pooled andlyophilized to afford6-(2-amino-3-fluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamideas a 2,2,2-trifluoroacetic acid salt (Example 26).

The following compounds were prepared using a similar procedure:

Example Name MS NMR 24 6-(2-aminopyridin-4- 477.2 1H NMR (400 MHz,DMSO-d6) yl)-1-(5,8- δ 9.29 (d, J = 4.5 Hz, 1H), difluoroquinolin-4-9.16 (d, J = 3.3 Hz, 1H), 8.17 (t, J = 1.6 Hz, yl)-2- 1H), 8.08 (d, J =4.5 Hz, methylbenzimidazole- 1H), 8.02 (d, J = 3.2 Hz, 1H),4-carboxamide 7.77 (td, J = 9.5, 4.2 Hz, 1H), 7.71 (d, J = 6.0 Hz, 1H),7.56 (d, J = 1.6 Hz, 1H), 7.45 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 6.78(t, J = 5.7 Hz, 1H), 2.68 (td, J = 7.4, 1.7 Hz, 2H), 1.72 (h, J = 7.4Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H). 25 6-(2-aminopyridin-4- 491.2 1H NMR(400 MHz, DMSO-d6) yl)-1-(8-chloro-5- δ 9.37 (d, J = 4.5 Hz, 1H),fluoroquinolin-4-yl)- 8.97 (d, J = 3.3 Hz, 1H), 2- 8.18-8.08 (m, 3H),7.94 (d, J = 3.3 Hz, 1H), methylbenzimidazole- 7.73-7.68 (m, 1H), 7.57(s, 1H), 4-carboxamide 7.49 (dd, J = 11.8, 8.6 Hz, 1H), 6.78 (t, J = 5.9Hz, 1H), 1.80-1.72 (m, 1H), 1.30-1.23 (d, J = 5.6 Hz, 1H), 1.20-1.11 (m,1H), 1.07-0.93 (m, 2H). 26 6-(2-aminopyrimidin- 449.1 1H NMR (400 MHz,DMSO-d6) 4-yl)-1-(8- δ 9.29 (d, J = 4.5 Hz, 1H), chloroquinolin-4-yl)-9.10 (d, J = 3.2 Hz, 1H), 8.17 (t, J = 1.7 Hz, 2- 1H), 8.07 (d, J = 4.5Hz, methylbenzimidazole- 1H), 8.02 (d, J = 3.2 Hz, 1H), 4-carboxamide7.82-7.74 (m, 1H), 7.71 (d, J = 6.0 Hz, 1H), 7.57 (t, J = 1.3 Hz, 1H),7.46 (ddd, J = 12.4, 8.8, 3.9 Hz, 1H), 6.80 (t, J = 5.8 Hz, 1H), 2.45(s, 3H).

Preparation of the Compounds of Formula (5) According to Reaction Scheme3 A. Preparation of Ethyl6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate

A solution ethyl2-amino-5-bromo-3-((5,8-difluoroquinolin-4-yl)amino)benzoate (3.7 g,8.76 mmol, made as described above) in trimethyl orthoformate (50 mL)was refluxed for 30 minutes. Upon cooling, the mixture was concentratedunder reduced pressure. The resulting solid was triturated with 25 mL ofdiethyl ether. The solid was recovered by filtration to afford ethyl6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate.ES/MS m/z=432.0 (M+H⁺).

B. Preparation of6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylicAcid

Aqueous 1M lithium hydroxide (3.4 mL) was added to ethyl6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate(1.19 g, 2.75 mmol) in THF (15 mL). The reaction was stirred at ambienttemperature for 1 hour. The reaction mixture was acidified with 4N HClin dioxane. The resulting solution was concentrated under reducedpressure to afford6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylicacid which was used without further purification for the next step.ES/MS m/z 404.0 (M+H)⁺.

C. Preparation of6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide

To a solution of6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylicacid (1.11 g, 2.75 mmol) in DMF (9.0 mL) were added ammonium chloride(1.03 g, 19.2 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (2.10 g, 11.0 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (2.10 g, 11.0 mmol) and diethylisopropylamine (4.8 mL,27.5 mmol). The mixture was stirred at 50° C. for overnight. Thematerial was precipitated with the addition of water. The resultingsolid was filtered, washed with water, and dried under high vacuum toafford6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamideES/MS m/z 403.0 (M+H)⁺.

D. Preparation of1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazole-4-carboxamide

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (276 mg, 0.34 mmol) was added to a solution of6-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide(910 mg, 2.26 mmol), bis(neopentyl glycolato)diboron (663 mg, 2.93 mmol)and potassium acetate (554 mg, 5.64 mmol) in dioxane (20 mL). Nitrogenwas bubbled for 10 minutes and the reaction mixture was stirred atrefluxing temperature for 24 hours. The reaction mixture was cooled toambient temperature and the solid was filtered. The solid was washedwith water and dried under vacuum to afford1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazole-4-carboxamideES/MS m/z=369.2 (ArB(OH)₂+H)⁺.

E. Preparation of6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide

Tetrakis(triphenylphosphine)palladium(0) (146 mg, 0.13 mmol) was addedto a solution of1-(5,8-difluoroquinolin-4-yl)-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazole-4-carboxamide(550 mg, 1.26 mmol), 4-iodo-2,3-difluoropyridine (365 mg, 1.51 mmol),and potassium phosphate tribasic (669 mg, 3.15 mmol) in dioxane (6.0 mL)and water (1.5 mL). Nitrogen was bubbled for 10 minutes and the reactionmixture was stirred at 100° C. for 4 hours. Upon cooling, the reactionmixture was partitioned between ethyl acetate and water. The organicphase was washed with brine, dried with magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography eluting with 5 to 100% of (10% methanolin ethyl acetate) in hexane to afford6-(2,3-difluoropyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide.ES/MS m/z=438.2 (M+H)⁺.

Preparation of Compounds of Formula (IM) A. Preparation of4-(6-(2-(difluoromethyl)pyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)-5,8-difluoroquinoline

6-(2-(difluoromethyl)pyridin-4-yl)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide(455 mg, 0.98 mmol) was suspended in1,1-dimethoxy-N,N-dimethylmethanamine (6.5 mL, 49 mmol) and stirred at100° C. for 5 hours. The solution was cooled to ambient temperature,concentrated under reduced pressure and dried under vacuum overnight.The residue was dissolved in acetic acid (5 mL) and hydrazine (92 μL,2.93 mmol) was added. The reaction mixture was stirred at 45° C. for 1hour, after which the reaction was cooled to ambient temperature andconcentrated under reduced pressure. The resultant was purified by HPLCeluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid).The appropriate fractions were pooled and lyophilized to afford4-(6-(2-(difluoromethyl)pyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)-5,8-difluoroquinolineas a 2,2,2-trifluoroacetic acid salt (Example 43).

The following compounds were prepared using a similar procedure:

-   tert-butyl    4-(4-(6-(2-cyanopyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate-   4-(4-(4H-1,2,4-triazol-3-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazol-6-yl)picolinonitrile

Example Name MS NMR 27 8-chloro-4-[6-pyridin-4- 424.0 1H NMR (400 MHz,DMSO-d6) yl-4-(1H-1,2,4-triazol-5- δ 9.34-9.26 (m, 1H), 9.02 (s,yl)benzimidazol-1- 1H), 8.77-8.71 (m, 2H), yl]quinoline 8.48 (d, J = 1.7Hz, 1H), 8.39 (s, 1H), 8.14-8.06 (m, 4H), 7.99 (d, J = 1.7 Hz, 1H), 7.63(dd, J = 8.5, 7.4 Hz, 1H), 7.55 (dd, J = 8.5, 1.3 Hz, 1H). 285,8-difluoro-4-[2- 440.1 1H NMR (400 MHz, DMSO-d6)methyl-6-pyridin-4-yl- δ 9.33 (d, J = 4.5 Hz, 1H),4-(4H-1,2,4-triazol-3- 8.78-8.73 (m, 2H), 8.46 (dd, J = 1.8,yl)benzimidazol-1- 0.6 Hz, 1H), 8.23-8.16 (m, 2H), yl]quinoline 8.09 (d,J = 4.5 Hz, 1H), 7.91 (dd, J = 1.8, 0.6 Hz, 1H), 7.79 (td, J = 9.5, 4.2Hz, 1H), 7.47 (ddd, J = 12.3, 8.7, 3.8 Hz, 1H), 2.50 (s, 3H). 295,8-dichloro-4-[2- 472.1 1H NMR (400 MHz, DMSO-d6)methyl-6-pyridin-4-yl- δ 9.40 (dd, J = 4.4, 0.6 Hz, 1H),4-(4H-1,2,4-triazol-3- 8.76-8.71 (m, 2H), 8.46 (d, J = 1.7 Hz,yl)benzimidazol-1- 1H), 8.17 (d, J = 5.9 Hz, yl]quinoline 2H), 8.12 (dd,J = 8.3, 0.6 Hz, 1H), 8.09 (dd, J = 4.4, 0.7 Hz, 1H), 7.86 (d, J = 1.7Hz, 1H), 7.77 (dd, J = 8.3, 0.6 Hz, 1H), 2.45 (s, 3H). 305-fluoro-4-[2-methyl-6- 422.1 1H NMR (400 MHz, DMSO-d6)pyridin-4-yl-4-(4H- δ 9.32-9.25 (m, 1H), 8.80 (dt, J = 5.6,1,2,4-triazol-3- 0.8 Hz, 2H), 8.52 (s, 1H), yl)benzimidazol-1- 8.50 (dd,J = 1.8, 0.7 Hz, 1H), yl]quinoline 8.31-8.27 (m, 2H), 8.17 (dd, J = 8.5,0.9 Hz, 1H), 7.99 (dd, J = 4.5, 0.7 Hz, 1H), 7.95-7.93 (m, 1H),7.93-7.88 (m, 1H), 7.47 (ddd, J = 12.4, 7.9, 0.9 Hz, 1H), 2.51 (s, 3H).31 5-methyl-4-[2-methyl-6- 418.1 1H NMR (400 MHz, DMSO-d6)pyridin-4-yl-4-(4H- δ 9.18 (d, J = 4.4 Hz, 1H), 1,2,4-triazol-3-8.79-8.75 (m, 2H), 8.50 (dd, J = 1.7, yl)benzimidazol-1- 0.6 Hz, 1H),8.28-8.25 (m, 2H), yl]quinoline 8.18-8.14 (m, 1H), 7.84-7.76 (m, 4H),7.48 (d, J = 7.0 Hz, 1H), 2.43 (s, 3H), 1.76 (s, 3H). 328-chloro-2-methyl-4-[2- 452.1 1H NMR (400 MHz, DMSO-d6)methyl-6-pyridin-4-yl- δ 8.68 (d, J = 5.9 Hz, 2H),4-(4H-1,2,4-triazol-3- 8.43 (s, 1H), 8.03 (d, J = 7.2 Hz, 3H),yl)benzimidazol-1- 7.95 (s, 1H), 7.75 (s, 1H), yl]quinoline 7.49 (s,1H), 7.24 (d, J = 8.7 Hz, 1H), 2.84 (s, 3H). 33 5,8-difluoro-4-[2- 454.21H NMR (400 MHz, DMSO-d6) methyl-4-(5-methyl-4H- δ 9.33 (d, J = 4.5 Hz,1H), 1,2,4-triazol-3-yl)-6- 8.76-8.73 (m, 2H), 8.42 (d, J = 1.8 Hz,pyridin-4- 1H), 8.21-8.16 (m, 2H), ylbenzimidazol-1- 8.09 (d, J = 4.5Hz, 1H), 7.89 (d, J = 1.8 Hz, yl]quinoline 1H), 7.79 (ddd, J = 10.1,8.8, 4.3 Hz, 1H), 7.47 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 2.50 (s, 3H),2.47 (s, 3H). 34 2-methyl-4-[2-methyl-6- 418.2 1H NMR (400 MHz, DMSO-d6)pyridin-4-yl-4-(4H- δ 8.84-8.77 (m, 3H), 8.58 (s, 1,2,4-triazol-3- 1H),8.53 (d, J = 1.7 Hz, 1H), yl)benzimidazol-1- 8.28-8.24 (m, 2H), 8.19(dt, J = 8.5, yl]quinoline 1.0 Hz, 1H), 7.94-7.82 (m, 3H), 7.56 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.40-7.35 (m, 1H), 2.82 (s, 3H), 2.54 (s, 3H).35 8-chloro-4-[2-methyl-4- 452.2 1H NMR (400 MHz, DMSO-d6)(5-methyl-4H-1,2,4- δ 9.34 (dd, J = 8.2, 4.5 Hz, 1H),triazol-3-yl)-6-pyridin- 8.70 (ddd, J = 4.9, 3.5, 1.9 Hz,4-ylbenzimidazol-1- 5H), 8.43 (d, J = 1.8 Hz, 1H), yl]quinoline 8.34 (d,J = 1.8 Hz, 1H), 8.13-8.05 (m, 8H), 8.02 (dd, J = 4.6, 1.2 Hz, 1H), 7.90(d, J = 1.8 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.62-7.58 (m, 1H),7.58-7.53 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.4, 1.3 Hz,1H), 4.00 (s, 3H), 2.43 (s, 3H). 36 8-chloro-4-[2-(oxetan-3- 480.2 1HNMR (400 MHz, DMSO-d6) yl)-6-pyridin-4-yl-4- δ 9.34-9.28 (m, 1H),(4H-1,2,4-triazol-3- 8.77-8.70 (m, 3H), 8.51 (d, J = 1.8 Hz,yl)benzimidazol-1- 1H), 8.16 (d, J = 5.9 Hz, 3H), yl]quinoline 8.09 (dd,J = 7.5, 1.3 Hz, 1H), 7.96 (d, J = 4.5 Hz, 1H), 7.80 (d, J = 1.7 Hz,1H), 7.55 (dd, J = 8.5, 7.5 Hz, 1H), 7.24 (dd, J = 8.5, 1.3 Hz, 1H),5.16 (dt, J = 35.1, 6.2 Hz, 2H), 4.69 (dd, J = 8.6, 5.6 Hz, 1H), 4.51(dd, J = 8.5, 5.5 Hz, 1H), 4.32-4.22 (m, 1H). 37 8-chloro-5-fluoro-4-[2-456.1 1H NMR (400 MHz, DMSO-d6) methyl-6-pyridin-4-yl- δ 9.39 (d, J =4.5 Hz, 1H), 4-(4H-1,2,4-triazol-3- 9.10 (d, J = 3.1 Hz, 1H),yl)benzimidazol-1- 8.75-8.68 (m, 2H), 8.42 (d, J = 1.8 Hz, 1H),yl]quinoline 8.15-8.04 (m, 5H), 7.96 (d, J = 1.8 Hz, 1H), 7.46 (dd, J =11.9, 8.5 Hz, 1H), 2.46 (s, 3H). 38 8-chloro-4-[2-methyl-6- 438.1 1H NMR(400 MHz, DMSO-d6) pyridin-4-yl-4-(4H- δ 9.34 (d, J = 4.5 Hz, 1H),1,2,4-triazol-3- 8.71-8.67 (m, 2H), 8.44 (d, J = 1.8 Hz,yl)benzimidazol-1- 1H), 8.10 (dd, J = 7.5, 1.2 Hz, yl]quinoline 1H),8.05 (dd, J = 10.9, 5.1 Hz, 3H), 7.74 (d, J = 1.7 Hz, 1H), 7.59 (dd, J =8.5, 7.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 2.47 (s, 3H). 398-chloro-4-[6-(3- 456.1 1H NMR (400 MHz, DMSO-d6) fluoropyridin-4-yl)-2-δ 9.33 (dd, J = 4.5, 0.6 Hz, 1H), methyl-4-(4H-1,2,4- 8.60 (d, J = 2.6Hz, 1H), 8.51 (s, triazol-3- 1H), 8.43-8.39 (m, 1H), yl)benzimidazol-1-8.30 (d, J = 1.9 Hz, 1H), 8.11 (dt, J = 7.4, yl]quinoline 1.0 Hz, 1H),8.08 (d, J = 4.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.49 (s, 1H), 7.42 (d, J =8.4 Hz, 1H), 2.54 (s, 3H). 40 8-chloro-4-[2-methyl-6- 425.1 1H NMR (400MHz, DMSO-d6) (2-methylpyridin-4-yl)- δ 9.36 (dd, J = 4.5, 0.6 Hz, 1H),4-(4H-1,2,4-triazol-3- 8.67 (d, J = 6.2 Hz, 1H), 8.50 (d,yl)benzimidazol-1- J = 1.8 Hz, 1H), 8.46 (s, 1H), yl]quinoline 8.20 (s,1H), 8.14-8.05 (m, 3H), 7.80 (d, J = 1.7 Hz, 1H), 7.59 (ddd, J = 8.4,7.5, 0.6 Hz, 1H), 7.33 (dt, J = 8.5, 0.9 Hz, 1H), 2.65 (s, 3H), 2.48 (s,3H). 41 4-[6-(2,5- 476.2 1H NMR (400 MHz, DMSO-d6)difluoropyridin-4-yl)-2- δ 9.32 (d, J = 4.5 Hz, 1H), methyl-4-(4H-1,2,4-8.45 (s, 1H), 8.30-8.29 (m, 1H), triazol-3- 8.28-8.27 (m, 1H), 8.09 (d,J = 4.5 Hz, yl)benzimidazol-1-yl]- 1H), 7.82-7.75 (m, 1H),5,8-difluoroquinoline 7.64 (s, 1H), 7.51-7.43 (m, 2H), 2.52 (s, 3H). 424-[6-(2,3- 476.1 1H NMR (400 MHz, DMSO-d6) difluoropyridin-4-yl)-2- δ9.31 (d, J = 4.5 Hz, 1H), methyl-4-(4H-1,2,4- 8.42 (brs, 1H), 8.24 (t, J= 1.6 Hz, triazol-3- 1H), 8.09 (d, J = 4.5 Hz, 1H),yl)benzimidazol-1-yl]- 8.01 (dd, J = 5.3, 1.1 Hz, 1H),5,8-difluoroquinoline 7.83-7.74 (m, 1H), 7.60 (t, J = 1.3 Hz, 1H), 7.56(t, J = 5.1 Hz, 1H), 7.47 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 2.51 (s,3H). 43 4-[6-[2- 490.1 1H NMR (400 MHz, DMSO-d6)(difluoromethyl)pyridin- δ 9.34 (d, J = 4.5 Hz, 1H),4-yl]-2-methyl-4-(4H- 8.66 (dd, J = 5.2, 0.7 Hz, 1H), 8.53 (s,1,2,4-triazol-3- 1H), 8.41 (d, J = 1.7 Hz, 1H), yl)benzimidazol-1-yl]-8.11 (d, J = 4.5 Hz, 1H), 5,8-difluoroquinoline 7.97 (dd, J = 1.9, 0.7Hz, 1H), 7.91-7.87 (m, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.79 (ddd, J =10.0, 8.8, 4.2 Hz, 1H), 7.48 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 6.96 (t,J = 54.8 Hz, 1H), 2.53 (s, 3H). 44 4-[3-(5,8- 465.1 1H NMR (400 MHz,DMSO-d6) difluoroquinolin-4-yl)- δ 9.34 (d, J = 4.5 Hz, 1H),2-methyl-7-(4H-1,2,4- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.50 (s,triazol-3- 1H), 8.43 (d, J = 1.7 Hz, 1H), yl)benzimidazol-5- 8.39 (dd, J= 2.0, 0.8 Hz, 1H), yl]pyridine-2- 8.11-8.07 (m, 2H), 7.87 (d, J = 1.7Hz, carbonitrile 1H), 7.79 (ddd, J = 10.1, 8.8, 4.3 Hz, 1H), 7.48 (ddd,J = 12.3, 8.8, 3.8 Hz, 1H), 2.52 (s, 3H). 45 5,8-difluoro-4-[2- 454.2 1HNMR (400 MHz, DMSO-d6) methyl-6-(2- δ 9.34 (d, J = 4.5 Hz, 1H),methylpyridin-4-yl)-4- 8.70 (dd, J = 6.4, 0.6 Hz, 1H), 8.48 (d,(4H-1,2,4-triazol-3- J = 1.8 Hz, 1H), 8.44 (s, 1H), yl)benzimidazol-1-8.25 (d, J = 1.9 Hz, 1H), yl]quinoline 8.15 (dd, J = 6.3, 2.0 Hz, 1H),8.10 (d, J = 4.5 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.79 (ddd, J = 10.0,8.8, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.67 (s, 3H),2.48 (s, 3H). 46 5,8-difluoro-4-[6-(2- 472.2 1H NMR (400 MHz, DMSO-d6)fluoro-3-methylpyridin- δ 9.28 (d, J = 4.5 Hz, 1H),4-yl)-2-methyl-4-(4H- 8.08 (d, J = 4.5 Hz, 1H), 8.03 (d, J = 5.0 Hz,1,2,4-triazol-3- 1H), 7.95 (d, J = 1.6 Hz, yl)benzimidazol-1- 1H),7.81-7.73 (m, 1H), yl]quinoline 7.51-7.44 (m, 1H), 7.38 (s, 1H), 7.24(d, J = 5.0 Hz, 1H), 2.53 (s, 3H), 2.07 (s, 3H). 47 4-[6-(2,3- 462.1 1HNMR (400 MHz, DMSO-d6) difluoropyridin-4-yl)-4- δ 9.26 (d, J = 4.5 Hz,1H), (4H-1,2,4-triazol-3- 8.98 (d, J = 2.6 Hz, 1H), 8.37 (s, 1H),yl)benzimidazol-1-yl]- 8.29 (t, J = 1.6 Hz, 1H), 8.07 (d,5,8-difluoroquinoline J = 4.6 Hz, 1H), 8.04 (dd, J = 5.1, 1.1 Hz, 1H),7.83 (d, J = 1.4 Hz, 1H), 7.82-7.74 (m, 1H), 7.61 (t, J = 5.1 Hz, 1H),7.49 (ddd, J = 12.4, 8.8, 3.9 Hz, 1H). 143 4-(1-(5,7- 465.2 1H NMR (400MHz, DMSO-d6) difluoroquinolin-4-yl)- δ 9.31 (d, J = 4.6 Hz, 1H),2-methyl-4-(4H-1,2,4- 8.72 (dd, J = 5.3, 0.8 Hz, 1H), triazol-3-yl)-1H-8.55-8.49 (m, 1H), 8.43 (d, J = 1.7 Hz, benzo[d]imidazol-6- 1H), 8.40(dd, J = 1.9, 0.8 Hz, yl)picolinonitrile 1H), 8.09 (dd, J = 5.3, 2.0 Hz,1H), 8.00 (ddd, J = 9.7, 2.5, 1.3 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H),7.86 (d, J = 1.7 Hz, 1H), 7.66 (ddd, J = 12.1, 9.3, 2.5 Hz, 1H), 2.52(t, J = 0.5 Hz, 3H). 144 4-(1-(5-chloro-8- 481.1 1H NMR (400 MHz,DMSO-d6) fluoroquinolin-4-yl)-2- δ 9.35 (d, J = 4.4 Hz, 1H),methyl-4-(4H-1,2,4- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.51 (s,triazol-3-yl)-1H- 1H), 8.45 (d, J = 1.8 Hz, 1H), benzo[d]imidazol-6-8.40 (dd, J = 1.9, 0.8 Hz, 1H), yl)picolinonitrile 8.12-8.07 (m, 2H),7.83 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.80 (s, 1H), 2.48(s, 3H). 145 4-(1-(5,8- 497.1 1H NMR (400 MHz, DMSO-d6)dichloroquinolin-4-yl)- δ 9.42 (d, J = 4.4 Hz, 1H),2-methyl-4-(4H-1,2,4- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.55 (s,triazol-3-yl)-1H- 1H), 8.46 (d, J = 1.7 Hz, 1H), benzo[d]imidazol-6-8.40 (dd, J = 2.0, 0.8 Hz, 1H), yl)picolinonitrile 8.15-8.07 (m, 3H),7.86 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 2.50 (s, 3H). 1464-(1-(5-chloroquinolin- 463.1 1H NMR (400 MHz, DMSO-d6)4-yl)-2-methyl-4-(4H- δ 9.27 (d, J = 4.6 Hz, 1H),1,2,4-triazol-3-yl)-1H- 8.70 (dd, J = 5.3, 0.8 Hz, 1H), 8.40 (d,benzo[d]imidazol-6- J = 1.8 Hz, 1H), 8.38 (dd, J = 2.0,yl)picolinonitrile 0.8 Hz, 1H), 8.37-8.35 (m, 1H), 8.06 (dd, J = 5.3,1.9 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.65(dd, J = 9.0, 2.2 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 2.47 (s, 3H). 1474-(1-(5-fluoroquinolin- 447.1 1H NMR (400 MHz, DMSO-d6)4-yl)-2-methyl-4-(4H- δ 9.30 (d, J = 4.5 Hz, 1H),1,2,4-triazol-3-yl)-1H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.57 (s,benzo[d]imidazol-6- 1H), 8.46 (d, J = 1.7 Hz, 1H), yl)picolinonitrile8.41 (dd, J = 2.0, 0.8 Hz, 1H), 8.19-8.15 (m, 1H), 8.09 (dd, J = 5.3,1.9 Hz, 1H), 8.00 (d, J = 4.6 Hz, 1H), 7.95-7.87 (m, 2H), 7.48 (ddd, J =12.4, 7.9, 1.0 Hz, 1H), 2.53 (s, 3H). 148 4-(1-(8-fluoroquinolin- 447.11H NMR (400 MHz, DMSO-d6) 4-yl)-2-methyl-4-(4H- δ 9.30 (d, J = 4.5 Hz,1H), 1,2,4-triazol-3-yl)-1H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.58 (s,benzo[d]imidazol-6- 1H), 8.48 (d, J = 1.7 Hz, 1H), yl)picolinonitrile8.39 (dd, J = 2.0, 0.8 Hz, 1H), 8.10-8.04 (m, 2H), 7.81 (d, J = 1.7 Hz,1H), 7.76 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H), 7.61 (td, J = 8.1, 5.0 Hz,1H), 7.32-7.24 (m, 1H), 2.54 (s, 3H). 149 4-(1-(8-chloroquinolin- 463.01H NMR (400 MHz, DMSO-d6) 4-yl)-2-methyl-4-(4H- δ 9.36 (d, J = 4.5 Hz,1H), 1,2,4-triazol-3-yl)-1H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.58 (s,benzo[d]imidazol-6- 1H), 8.48 (d, J = 1.7 Hz, 1H), yl)picolinonitrile8.38 (dd, J = 2.0, 0.8 Hz, 1H), 8.11 (dd, J = 7.5, 1.2 Hz, 1H),8.10-8.05 (m, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.5, 7.5 Hz,1H), 7.43 (dd, J = 8.5, 1.2 Hz, 1H), 2.53 (s, 3H). 150 4-(1-(8-chloro-5-495.1 1H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)-2- δ 9.41 (d, J =4.5 Hz, 1H), methyl-4-(5-methyl-4H- 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.40(d, 1,2,4-triazol-3-yl)-1H- J = 1.7 Hz, 1H), 8.38 (dd, J = 2.0,benzo[d]imidazol-6- 0.8 Hz, 1H), 8.16-8.10 (m, yl)picolinonitrile 2H),8.07 (dd, J = 5.3, 1.9 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.49 (dd, J =12.0, 8.6 Hz, 1H), 2.53 (s, 3H), 2.51 (s, 3H). 151 4-(1-(5,8- 479.2 1HNMR (400 MHz, DMSO-d6) difluoroquinolin-4-yl)- δ 9.35 (d, J = 4.5 Hz,1H), 2-methyl-4-(5-methyl- 8.71 (dd, J = 5.3, 0.8 Hz, 1H),4H-1,2,4-triazol-3-yl)- 8.42-8.37 (m, 2H), 8.10 (d, J = 4.5 Hz,1H-benzo[d]imidazol-6- 1H), 8.08 (dd, J = 5.3, 2.0 Hz,yl)picolinonitrile 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.80 (ddd, J = 10.0,8.8, 4.2 Hz, 1H), 7.48 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.52 (s, 3H),2.50 (s, 3H). 152 4-(1-(5,8- 466.1 1H NMR (400 MHz, DMSO-d6)difluoroquinolin-4-yl)- δ 9.34 (d, J = 4.5 Hz, 1H),2-methyl-4-(4H-1,2,4- 8.91 (d, J = 5.6 Hz, 1H), 8.87 (d, J = 1.7 Hz,triazol-3-yl)-1H- 1H), 8.43 (s, 1H), benzo[d]imidazol-6- 8.38 (d, J =5.6 Hz, 1H), 8.11 (d, J = 4.5 Hz, yl)pyrimidine-2- 1H), 8.08 (d, J = 1.7Hz, carbonitrile 1H), 7.83-7.76 (m, 1H), 7.47 (ddd, J = 12.3, 8.8, 3.8Hz, 1H). 153 4-(1-(8-chloro-5- 481.1 1H NMR (400 MHz, DMSO-d6)fluoroquinolin-4-yl)-2- δ 9.42 (d, J = 4.5 Hz, 1H), methyl-4-(4H-1,2,4-8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.53 (s, triazol-3-yl)-1H- 1H), 8.44 (d,J = 1.8 Hz, 1H), benzo[d]imidazol-6- 8.39 (dd, J = 1.9, 0.8 Hz, 1H),yl)picolinonitrile 8.16-8.11 (m, 2H), 8.08 (dd, J = 5.3, 1.9 Hz, 1H),7.89 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H), 2.53 (s, 3H).154 5,8-difluoro-4-(6-(2- 471.2 1H NMR (400 MHz, DMSO-d6)methoxypyrimidin-4- δ 9.34 (d, J = 4.5 Hz, 1H), yl)-2-methyl-4-(4H- 8.89(d, J = 1.6 Hz, 1H), 8.56 (d, J = 5.3 Hz, 1,2,4-triazol-3-yl)-1H- 1H),8.48 (s, 1H), benzo[d]imidazol-1- 8.12 (d, J = 4.5 Hz, 1H), 8.02 (d, J =1.6 Hz, yl)quinoline 1H), 7.84-7.76 (m, 1H), 7.71 (d, J = 5.3 Hz, 1H),7.48 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 3.93 (s, 3H), 2.52 (s, 3H). 1555,8-difluoro-4-(2- 455.2 1H NMR (400 MHz, DMSO-d6) methyl-6-(6- δ 9.39(d, J = 4.5 Hz, 1H), methylpyrimidin-4-yl)- 9.05 (d, J = 1.3 Hz, 1H),8.97 (d, J = 1.6 Hz, 4-(4H-1,2,4-triazol-3- 1H), 8.58 (s, 1H), yl)-1H-8.16 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 1.6 Hz, benzo[d]imidazol-1- 1H),8.01 (dd, J = 1.3, yl)quinoline 0.6 Hz, 1H), 7.83 (ddd, J = 10.0, 8.8,4.2 Hz, 1H), 7.52 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 2.57 (s, 3H), 2.47(s, 3H). 156 5,8-difluoro-4-(2- 455.2 1H NMR (400 MHz, DMSO-d6)methyl-6-(2- δ 9.37 (d, J = 4.5 Hz, 1H), methylpyrimidin-4-yl)- 8.95 (d,J = 1.6 Hz, 1H), 8.67 (d, J = 5.5 Hz, 4-(4H-1,2,4-triazol-3- 1H), 8.52(s, 1H), yl)-1H- 8.14 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 1.6 Hz,benzo[d]imidazol-1- 1H), 7.90 (dd, J = 5.5, yl)quinoline 0.7 Hz, 1H),7.82 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.50 (ddd, J = 12.4, 8.8, 3.8 Hz,1H), 2.66 (s, 3H), 2.55 (s, 3H). 158 4-(6-(2-chloropyridin-4- 474.1 1HNMR (400 MHz, DMSO-d6) yl)-2-methyl-4-(4H- δ 9.36 (d, J = 4.5 Hz, 1H),1,2,4-triazol-3-yl)-1H- 8.51 (s, 1H), 8.41 (dd, J = 5.3, 0.6 Hz,benzo[d]imidazol-1-yl)- 1H), 8.38 (dd, J = 1.8, 0.9 Hz,5,8-difluoroquinoline 1H), 8.11 (d, J = 4.6 Hz, 1H), 7.88-7.75 (m, 4H),7.50 (ddd, J = 12.3, 8.7, 3.8 Hz, 1H), 2.53 (d, J = 1.0 Hz, 3H). 1595,8-difluoro-4-(6-(2- 458.2 1H NMR (400 MHz, DMSO-d6)fluoropyridin-4-yl)-2- δ 9.35 (d, J = 4.5 Hz, 1H), methyl-4-(4H-1,2,4-8.50 (s, 1H), 8.42-8.37 (m, 1H), triazol-3-yl)-1H- 8.25 (d, J = 5.3 Hz,1H), 8.11 (d, benzo[d]imidazol-1- J = 4.5 Hz, 1H), 7.87-7.84 (m,yl)quinoline 1H), 7.81 (ddd, J = 9.8, 8.8, 4.2 Hz, 1H), 7.73 (dt, J =5.5, 1.8 Hz, 1H), 7.53 (s, 1H), 7.49 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H),2.53 (s, 3H).

Preparation of Compounds of Formula (IM) in which R³⁰═NH₂ A. Preparationof tert-butyl(4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate

tert-Butyl(4-(4-carbamoyl-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate(120 mg, 0.23 mmol) was suspended in1,1-dimethoxy-N,N-dimethylmethanamine (3.0 mL, 22.7 mmol) and stirred at100° C. for 3 hours. The solution was cooled to ambient temperature,concentrated under reduced pressure and dried under vacuum forovernight. The residue was dissolved in acetic acid (2 mL) and hydrazine(28 μL, 0.57 mmol) was added. The reaction mixture was stirred at 45° C.for 1 hour, after which the reaction was cooled to ambient temperatureand concentrated under reduced pressure. The resultant was purified byHPLC eluting with 5-95% water/acetonitrile (0.1% v/v trifluoroaceticacid). The appropriate fractions were pooled and lyophilized to affordtert-butyl(4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamateas a 2,2,2-trifluoroacetic acid salt. ES/MS m/z=553.2 (M+H)⁺.

tert-Butyl(4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate(35 mg of 2,2,2-trifluoroacetic acid salt, 0.06 mmol) was dissolved indichloromethane (0.6 mL) and trifluoroacetic acid (100 μL, 2.93 mmol)was added. The reaction mixture was stirred at ambient temperature for 1hour, after which the reaction was concentrated under reduced pressure.The resultant was dissolved in a mixture of acetonitrile and waterfollowed by lyophilization to afford4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-amineas a 2,2,2-trifluoroacetic acid salt (Example 58).

The following compounds were prepared using a similar procedure:

Example Name MS NMR 48 4-[3-(5,8-difluoroquinolin- 455.2 1H NMR (400MHz, DMSO- 4-yl)-2-methyl-7-(4H- d6) δ 9.32 (d, J = 4.5 Hz, 1H),1,2,4-triazol-3- 8.30 (d, J = 1.3 Hz, 1H), yl)benzimidazol-5- 8.07 (d, J= 4.7 Hz, 1H), 7.89 (d, J = 6.8 Hz, yl]pyridin-2-amine 1H), 7.87-7.74(m, 4H), 7.69 (s, 1H), 7.52-7.36 (m, 1H), 7.26-7.19 (m, 2H). 494-[3-(8-chloroquinolin-4- 467.2 1H NMR (400 MHz, DMSO-yl)-2-methyl-7-(5-methyl- d6) δ 9.34 (dt, J = 4.6, 0.9 Hz,4H-1,2,4-triazol-3- 1H), 8.31 (d, J = 1.9 Hz, 1H), yl)benzimidazol-5-8.13-8.08 (m, 1H), 8.05 (dd, yl]pyridin-2-amine J = 4.6, 1.0 Hz, 1H),7.87 (d, J = 7.0 Hz, 2H), 7.63-7.53 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H),7.23 (s, 1H), 7.18 (d, J = 7.1 Hz, 1H). 50 4-[3-(8-chloro-5- 485.2 1HNMR (400 MHz, DMSO- fluoroquinolin-4-yl)-2- d6) δ 9.38 (d, J = 4.5 Hz,1H), methyl-7-(5-methyl-4H- 8.29 (d, J = 1.8 Hz, 1H), 1,2,4-triazol-3-8.12 (dd, J = 8.6, 5.0 Hz, 1H), yl)benzimidazol-5- 8.08 (d, J = 4.5 Hz,1H), 7.88 (d, J = 6.8 Hz, yl]pyridin-2-amine 1H), 7.69 (d, J = 1.7 Hz,1H), 7.48 (dd, J = 11.9, 8.5 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J = 6.7 Hz,1H), 2.46 (s, 3H), 2.45 (s, 3H). 51 4-[3-(8-chloro-5- 471.2 1H NMR (400MHz, DMSO- fluoroquinolin-4-yl)-2- d6) δ 9.39 (d, J = 4.5 Hz, 1H),methyl-7-(4H-1,2,4-triazol- 8.44 (s, 1H), 8.33 (d, J = 1.7 Hz,3-yl)benzimidazol-5- 1H), 8.13 (dd, J = 8.5, 5.0 Hz, yl]pyridin-2-amine1H), 8.09 (d, J = 4.5 Hz, 1H), 7.95 (s, 2H), 7.93 (s, 1H), 7.90 (d, J =6.8 Hz, 7H), 7.74 (d, J = 1.8 Hz, 1H), 7.48 (dd, J = 11.9, 8.6 Hz, 1H),7.25 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 6.9, 1.8 Hz, 2H), 3.18 (d, J =46.3 Hz, 1H), 2.87 (s, 3H), 2.71 (s, 3H). 52 4-[2-ethyl-3-(7- 451.2 1HNMR (400 MHz, DMSO- fluoroquinolin-4-yl)-7- d6) δ 9.25 (d, J = 4.6 Hz,1H), (4H-1,2,4-triazol-3- 8.44 (s, 1H), 8.35 (d, J = 1.8 Hz,yl)benzimidazol-5- 1H), 8.06 (dd, J = 10.0, yl]pyridin-2-amine 2.6 Hz,1H), 7.94 (d, J = 4.6 Hz, 1H), 7.89 (d, J = 6.5 Hz, 2H), 7.54 (d, J =1.8 Hz, 1H), 7.41 (dd, J = 9.3, 6.0 Hz, 1H), 7.20 (dd, J = 8.4, 1.6 Hz,2H), 2.72 (ddt, J = 23.9, 16.1, 7.9 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H).53 4-[3-(7-fluoroquinolin-4- 437.2 1H NMR (400 MHz, DMSO-yl)-2-methyl-7-(4H-1,2,4- d6) δ 9.26 (d, J = 4.5 Hz, 1H),triazol-3-yl)benzimidazol- 8.55 (s, 1H), 8.39 (d, J = 1.7 Hz,5-yl]pyridin-2-amine 1H) 8.07 (dd, J = 10.1, 2.5 Hz, 1H), 8.00-7.89 (m,2H), 7.62-7.45 (m, 3H), 7.24-7.16 (m, 2H), 2.52 (s, 3H). 544-[2-ethyl-3-(5- 451.2 1H NMR (400 MHz, DMSO- fluoroquinolin-4-yl)-7-d6) δ 9.28 (d, J = 4.5 Hz, 1H), (4H-1,2,4-triazol-3- 8.48 (s, 1H), 8.35(d, J = 1.7 Hz, yl)benzimidazol-5- 1H), 8.16 (dd, J = 8.6, 1.0 Hz,yl]pyridin-2-amine 1H), 8.03-7.82 (m, 5H), 7.69 (d, J = 1.7 Hz, 1H),7.50-7.42 (m, 1H), 7.23 (dd, J = 8.4, 1.5 Hz, 2H), 2.74 (qd, J = 7.8,4.7 Hz, 2H), 2.05 (s, 1H), 1.26 (t, J = 7.5 Hz, 3H). 554-[3-(5-fluoroquinolin-4- 437.2 1H NMR (400 MHz, DMSO-yl)-2-methyl-7-(4H-1,2,4- d6) δ 9.28 (d, J = 4.5 Hz, 1H),triazol-3-yl)benzimidazol- 8.47 (s, 1H), 8.34 (d, J = 1.7 Hz,5-yl]pyridin-2-amine 1H), 8.19-8.12 (m, 1H), 7.97 (d, J = 4.5 Hz, 1H),7.94-7.87 (m, 5H), 7.70 (d, J = 1.7 Hz, 1H), 7.47 (dd, J = 12.4, 7.8 Hz,1H), 7.24 (d, J = 6.5 Hz, 2H). 56 4-[3-(8-chloroquinolin-4- 454.1 1H NMR(400 MHz, DMSO- yl)-2-methyl-7-(4H-1,2,4- d6) δ 9.36 (d, J = 4.5 Hz,1H), triazol-3-yl)benzimidazol- 8.86 (d, J = 1.6 Hz, 1H),5-yl]pyrimidin-2-amine 8.48 (s, 1H), 8.24 (d, J = 5.8 Hz, 1H) 8.12 (dd,J = 7.6, 1.2 Hz, 1H), 8.09 (d, J = 4.5 Hz, 1H), 7.87 (d, J = 1.6 Hz,1H), 7.64-7.56 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 5.8 Hz,1H), 2.50 (s, 3H). 57 6-[3-(8-chloroquinolin-4- 469.1 1H NMR (400 MHz,DMSO- yl)-2-methyl-7-(4H-1,2,4- d6) δ 11.89 (s, 1H), 9.35 (d, J = 4.5Hz, triazol-3-yl)benzimidazol- 1H), 8.44 (s, 1H), 5-yl]pyrimidine-2,4-8.30 (s, 1H), 8.16-7.99 (m, diamine 4H), 7.61 (dd, J = 8.5, 7.6 Hz, 1H),7.48 (s, 1H), 7.30 (dd, J = 8.6, 1.2 Hz, 1H), 6.29 (s, 1H), 2.47 (s,3H). 58 4-[3-(8-chloroquinolin-4- 453.1 1H NMR (400 MHz, DMSO-yl)-2-methyl-7-(4H-1,2,4- d6) δ 9.34 (d, J = 4.5 Hz, 1H),triazol-3-yl)benzimidazol- 8.42 (s, 1H), 8.34 (d, J = 1.7 Hz,5-yl]pyridin-2-amine 1H), 8.11 (dd, J = 7.5, 1.2 Hz, 1H), 8.06 (d, J =4.5 Hz, 1H), 7.89 (d, J = 6.9 Hz, 2H), 7.65-7.55 (m, 2H), 7.30 (dd, J =8.5, 1.3 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 6.8, 1.8 Hz,1H), 2.47 (s, 3H). 59 6-[3-(8-chloroquinolin-4- 454.1yl)-2-methyl-7-(4H-1,2,4- triazol-3-yl)benzimidazol-5-yl]pyrimidin-4-amine 60 4-[2-cyclopropyl-3-(8- 463.2 1H NMR (400 MHz,DMSO- fluoroquinolin-4-yl)-7- d6) δ 9.28 (d, J = 4.5 Hz, 1H),(4H-1,2,4-triazol-3- 8.34 (d, J = 1.7 Hz, 1H), yl)benzimidazol-5- 8.08(d, J = 4.5 Hz, 1H), yl]pyridin-2-amine 7.91-7.86 (m, 1H), 7.83 (s, 2H),7.76 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H), 7.63 (td, J = 8.1, 5.0 Hz, 1H),7.57 (d, J = 1.7 Hz, 1H), 7.25-7.16 (m, 3H), 1.65 (td, J = 8.2, 4.3 Hz,1H), 1.60-1.41 (m, 2H), 1.08-0.97 (m, 1H), 0.98-0.88 (m, 1H). 614-[3-(8-fluoroquinolin-4- 437.2 1H NMR (400 MHz, DMSO-yl)-2-methyl-7-(4H-1,2,4- d6) δ 9.27 (d, J = 4.5 Hz,triazol-3-yl)benzimidazol- 1H), 8.34 (d, J = 1.8 Hz, 1H),5-yl]pyridin-2-amine 8.05 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 6.9 Hz, 1H),7.76 (ddd, J = 10.8, 7.7, 1.2 Hz, 1H), 7.61 (td, J = 8.1, 5.0 Hz, 1H),7.57 (d, J = 1.8 Hz, 1H), 7.23-7.21 (m, 1H), 7.19 (dd, J = 6.8, 1.9 Hz,1H), 7.15 (d, J = 8.5 Hz, 1H), 2.47 (s, J = 0.7 Hz, 3H). 624-[3-(8-chloro-5- 497.2 1H NMR (400 MHz, DMSO- fluoroquinolin-4-yl)-2-d6) δ 9.39 (d, J = 4.5 Hz, 1H), cyclopropyl-7-(4H-1,2,4- 8.32 (d, J =1.8 Hz, 1H), triazol-3-yl)benzimidazol- 8.15-8.09 (m, 2H),5-yl]pyridin-2-amine 7.91-7.86 (m, 1H), 7.82 (s, 2H), 7.69 (s, 1H), 7.49(dd, J = 11.9, 8.6 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 6.9,1.9 Hz, 1H), 1.71 (td, J = 8.2, 4.2 Hz, 1H), 1.49 (br s, 1H), 1.36 (brs, 1H), 1.04-0.88 (m, 2H). 63 4-[3-(8-chloro-5- 499.2 1H NMR (400 MHz,DMSO- fluoroquinolin-4-yl)-2- d6) δ 9.38 (d, J = 4.5 Hz,propyl-7-(4H-1,2,4-triazol- 1H), 8.31 (s, 1H), 8.12 (dd, J = 8.5,3-yl)benzimidazol-5- 4.9 Hz, 1H), 8.08 (d, J = 4.5 Hz,yl]pyridin-2-amine 1H), 7.88 (d, J = 6.7 Hz, 1H), 7.81 (br s, 1H), 7.68(br s, 1H), 7.47 (dd, J = 11.9, 8.5 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J =6.7 Hz, 1H), 2.67 (t, J = 7.5 Hz, 2H), 1.85-1.75 (m, 2H), 0.85 (t, J =7.4 Hz, 3H). 64 4-[3-(8-chloro-5- 511.1 1H NMR (400 MHz, DMSO-fluoroquinolin-4-yl)-2- d6) δ 9.39 (d, J = 4.5 Hz,cyclopropyl-7-(5-methyl- 1H), 8.28 (d, J = 1.8 Hz, 1H),4H-1,2,4-triazol-3- 8.15-8.09 (ABq, 2H), yl)benzimidazol-5- 7.92-7.85(m, 3H), 7.68 (d, J = 1.8 Hz, yl]pyridin-2-amine 1H), 7.49 (dd, J =11.9, 8.5 Hz, 1H), 7.27 (dd, J = 1.9, 0.7 Hz, 1H), 7.22 (dd, J = 6.9,1.9 Hz, 1H), 2.42 (s, 3H), 1.71 (ddd, J = 12.9, 8.3, 4.8 Hz, 1H),1.52-1.42 (m, 1H), 1.37-1.26 (m, 1H), 1.02-0.88 (m, 1H). 654-[3-(8-chloro-5- 513.2 1H NMR (400 MHz, DMSO-fluoroquinolin-4-yl)-7-(5- d6) δ 9.38 (d, J = 4.5 Hz,methyl-4H-1,2,4-triazol-3- 1H), 8.28 (d, J = 1.8 Hz, 1H),yl)-2-propylbenzimidazol- 8.12 (dd, J = 8.6, 4.9 Hz, 1H),5-yl]pyridin-2-amine 8.08 (d, J = 4.5 Hz, 1H), 7.87 (d, J = 6.9 Hz, 1H),7.84 (s, 2H), 7.66 (s, 1H), 7.47 (dd, J = 11.9, 8.6 Hz, 1H), 7.25 (s,1H), 7.21 (dd, J = 6.9, 1.8 Hz, 1H), 2.71-2.62 (m, 2H), 1.77-1.69 (m,2H), 0.84 (t, J = 7.4 Hz, 3H). 66 4-[3-(8-chloro-5- 513.2 1H NMR (400MHz, DMSO- fluoroquinolin-4-yl)-7-(5- d6) δ 9.38 (d, J = 4.5 Hz,methyl-4H-1,2,4-triazol-3- 1H), 8.28 (d, J = 1.8 Hz, 1H),yl)-2-propan-2- 8.15-8.09 (m, 2H), 7.86 (d, ylbenzimidazol-5- J = 6.8Hz, 1H), 7.84 (s, 2H), yl]pyridin-2-amine 7.65 (s, 1H), 7.47 (dd, J =11.9, 8.6 Hz, 1H), 7.25 (s, 1H), 7.21 (dd, J = 6.9, 1.8 Hz, 1H), 2.87(p, J = 6.8 Hz, 1H), 2.44 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.24 (d, J= 6.8 Hz, 3H). 67 4-[3-(8-chloro-5- 499.2 1H NMR (400 MHz, DMSO-fluoroquinolin-4-yl)-2- d6) δ 9.39 (d, J = 4.5 Hz,propan-2-yl-7-(4H-1,2,4- 1H), 8.32 (d, J = 1.8 Hz, 1H),triazol-3-yl)benzimidazol- 8.16-8.09 (m, 2H), 7.88 (d,5-yl]pyridin-2-amine J = 6.8 Hz, 1H), 7.84 (s, 2H), 7.68 (s, 1H), 7.48(dd, J = 11.9, 8.5 Hz, 1H), 7.24 (s, 1H), 7.21 (dd, J = 6.9, 1.8 Hz,1H), 2.88 (p, J = 6.7 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H), 1.26 (d, J =6.8 Hz, 3H). 68 4-[3-(8-chloro-5- 513.1 1H NMR (400 MHz, DMSO-fluoroquinolin-4-yl)-2- d6) δ 9.36 (d, J = 4.5 Hz,(oxetan-3-yl)-7-(4H-1,2,4- 1H), 8.37 (d, J = 1.8 Hz, 1H),triazol-3-yl)benzimidazol- 8.12 (dd, J = 8.5, 4.9 Hz, 1H),5-yl]pyridin-2-amine 8.01 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H),7.87 (s, 2H), 7.74 (s, 1H), 7.45 (dd, J = 12.0, 8.5 Hz, 1H), 7.28-7.24(m, 1H), 7.22 (dd, J = 6.9, 1.9 Hz, 1H), 5.15 (s, 2H), 4.63 (ddd, J =12.5, 8.6, 5.4 Hz, 2H), 4.34 (ddd, J = 15.6, 8.6, 7.0 Hz, 1H). 694-[2-cyclopropyl-3-(5,8- 481.2 1H NMR (400 MHz, DMSO-difluoroquinolin-4-yl)-7- d6) δ 9.32 (d, J = 4.5 Hz,(4H-1,2,4-triazol-3- 1H), 8.31 (d, J = 1.8 Hz, 1H), yl)benzimidazol-5-8.12 (d, J = 4.5 Hz, 1H), yl]pyridin-2-amine 7.92-7.83 (m, 3H),7.82-7.75 (m, 1H), 7.69 (s, 1H), 7.48 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H),7.26-7.24 (m, 1H), 7.22 (dd, J = 6.9, 1.9 Hz, 1H), 1.71 (td, J = 8.2,4.3 Hz, 1H), 1.50 (br s, 1H), 1.37 (br s, 1H), 1.04-0.89 (m, 2H). 704-[3-(5,8-difluoroquinolin- 469.2 1H NMR (400 MHz, DMSO-4-yl)-2-ethyl-7-(4H-1,2,4- d6) δ 9.31 (d, J = 4.5 Hz,triazol-3-yl)benzimidazol- 1H), 8.31 (d, J = 1.8 Hz, 1H),5-yl]pyridin-2-amine 8.09 (d, J = 4.5 Hz, 1H), 7.90-7.79 (m, 3H), 7.78(ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.69 (s, 1H), 7.46 (ddd, J = 12.3,8.8, 3.8 Hz, 1H), 7.25 (dd, J = 1.9, 0.7 Hz, 1H), 7.22 (dd, J = 6.9, 1.8Hz, 1H), 2.77-2.64 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H). 714-[2-(cyclopropylmethyl)- 495.2 1H NMR (400 MHz, DMSO-3-(5,8-difluoroquinolin-4- d6) δ 9.31 (d, J = 4.5 Hz, 1H),yl)-7-(4H-1,2,4-triazol-3- 8.32 (d, J = 1.7 Hz, 1H), yl)benzimidazol-5-8.08 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 6.8 Hz, yl]pyridin-2-amine 1H),7.87 (s, 2H), 7.83-7.72 (m, 1H), 7.69 (s, 1H), 7.44 (ddd, J = 12.3, 8.8,3.9 Hz, 1H), 7.28-7.19 (m, 2H), 2.73-2.66 (m, 1H), 0.41-0.22 (m, 2H),0.10-0.00 (m, 1H), −0.04-−0.13 (m, 1H). 72 4-[3-(5,8-difluoroquinolin-483.2 1H NMR (400 MHz, DMSO- 4-yl)-2-propyl-7-(4H- d6) δ 9.31 (d, J =4.5 Hz, 1H), 1,2,4-triazol-3- 8.31 (d, J = 1.7 Hz, 1H),yl)benzimidazol-5- 8.08 (d, J = 4.5 Hz, 1H), yl]pyridin-2-amine7.90-7.88 (m, 1H), 7.86 (s, 2H), 7.82-7.75 (m, 1H), 7.68 (s, 1H), 7.46(ddd, J = 12.3, 8.7, 3.7 Hz, 1H), 7.24 (t, J = 1.1 Hz, 1H), 7.22 (dd, J= 6.8, 1.9 Hz, 1H), 2.68 (t, J = 7.6 Hz, 2H), 1.84-1.73 (m, 2H), 0.85(t, J = 7.4 Hz, 3H). 73 4-[3-(8-chloroquinolin-4- 493.2 1H NMR (400 MHz,DMSO- yl)-2-(cyclopropylmethyl)- d6) δ 9.33 (d, J = 4.5 Hz, 1H),7-(4H-1,2,4-triazol-3- 8.35 (d, J = 1.7 Hz, 1H), yl)benzimidazol-5- 8.10(dd, J = 7.5, 1.2 Hz, 1H), yl]pyridin-2-amine 8.07 (d, J = 4.5 Hz, 1H),7.90-7.86 (m, 2H), 7.60-7.55 (m, 2H), 7.25-7.17 (m, 3H), 2.69 (d, J =6.9 Hz, 2H), 0.37-0.29 (m, 1H), 0.28-0.19 (m, 1H), 0.09-0.02 (m, 1H),−0.8-−0.14 (m, 1H). 74 4-[3-(8-chloroquinolin-4- 479.2 1H NMR (400 MHz,DMSO- yl)-2-cyclopropyl-7-(4H- d6) δ 9.35 (d, J = 4.5 Hz, 1H),1,2,4-triazol-3- 8.34 (s, 1H), 8.13-8.08 (m, yl)benzimidazol-5- 2H),7.88 (d, J = 6.8 Hz, 1H), yl]pyridin-2-amine 7.81 (br s, 2H), 7.64-7.57(m, 2H), 7.34 (dd, J = 8.4, 1.2 Hz, 1H), 7.23-7.18 (m, 2H), 1.69-1.61(m, 1H), 1.06-0.98 (m, 2H), 0.96-0.88 (m, 2H).

Preparation of Compounds of Formula (IC) in which R³⁰═NH₂ A. Preparationof4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)-3-fluoropyridin-2-amine

1-(8-chloroquinolin-4-yl)-6-(2,3-difluoropyridin-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide(130 mg, 0.29 mmol) was suspended in1,1-dimethoxy-N,N-dimethylmethanamine (1.9 mL, 14.4 mmol) and stirred at100° C. for 3 hours. The solution was cooled to ambient temperature,concentrated under reduced pressure and dried under vacuum forovernight. The residue was dissolved in acetic acid (3 mL) and hydrazine(18 μL, 0.58 mmol) was added. The reaction mixture was stirred at 45° C.for 1 hour, after which the reaction was cooled to ambient temperatureand concentrated under reduced pressure. The residue was taken up inethyl acetate, washed with saturated NaHCO₃, washed with brine, driedwith magnesium sulfate, filtered, and concentrated under reducedpressure. Crude8-chloro-4-(6-(2,3-difluoropyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)quinolinewas used without further purification in the next step. ES/MS m/z 474.2(M+H)⁺.

Ammonium hydroxide (28-30% solution in water, 0.75 mL) was added to asolution of crude8-chloro-4-(6-(2,3-difluoropyridin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)quinoline(0.274 mmol) in DMSO (3.0 mL). The reaction vessel was sealed and thereaction mixture was stirred at 100° C. overnight. The excess ammoniawas removed under reduced pressure and the resulting solution waspurified by HPLC eluting with 5-95% water/acetonitrile (0.1% v/vtrifluoroacetic acid). The appropriate fractions were pooled andlyophilized to afford4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)-3-fluoropyridin-2-amineas a 2,2,2-trifluoroacetic acid salt (Example 80).

The following compounds were synthesized using a similar method:

-   tert-butyl    4-(4-(6-(2-amino-3-fluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate

Example Name MS NMR 75 4-[3-(5,8- 473.2 1H NMR (400 MHz, DMSO-d6)difluoroquinolin-4- δ 9.31 (d, J = 4.5 Hz, 1H), yl)-2-methyl-7-(4H- 8.41(br s, 1H), 8.22 (s, 1H), 8.09 (d, J = 4.5 Hz, 1,2,4-triazol-3- 1H),7.78 (td, J = 9.5, yl)benzimidazol-5- 4.2 Hz, 1H), 7.74 (dd, J = 6.2,0.9 Hz, yl]-3-fluoropyridin-2- 1H), 7.52 (s, 1H), 7.47 (ddd, J = 12.3,amine 8.8, 3.8 Hz, 1H), 6.84 (br s, 1H), 2.51 (s, 3H). 76 4-[3-(5,8-473.2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4- δ 9.31 (d, J = 4.5Hz, 1H), yl)-2-methyl-7-(4H- 8.42 (br s, 1H), 8.17 (t, J = 1.8 Hz,1,2,4-triazol-3- 1H), 8.10 (s, 1H), 8.09 (s, 1H), yl)benzimidazol-5-7.83-7.75 (m, 1H), yl]-5-fluoropyridin-2- 7.53-7.43 (m, 2H), 6.82 (d, J= 6.0 Hz, 1H), amine 2.50 (s, 3H). 77 4-[3-(5,8- 487.2 1H NMR (400 MHz,DMSO-d6) difluoroquinolin-4- δ 9.31 (d, J = 4.5 Hz, 1H),yl)-2-methyl-7-(4H- 8.47 (s, 1H), 8.23 (t, J = 1.6 Hz, 1H),1,2,4-triazol-3- 8.10 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5- 7.83-7.75(m, 2H), 7.53 (s, 1H), yl]-3-fluoro-N- 7.48 (ddd, J = 12.3, 8.8, 3.8 Hz,1H), methylpyridin-2- 6.74 (t, J = 5.6 Hz, 1H), 2.87 (s, amine 3H), 2.53(s, 3H). 78 4-[3-(5,8- 501.2 1H NMR (400 MHz, DMSO-d6)difluoroquinolin-4- δ 9.30 (d, J = 4.5 Hz, 1H), yl)-2-propyl-7-(4H- 8.37(br s, 1H), 8.20 (d, J = 1.5 Hz, 1,2,4-triazol-3- 1H), 8.09 (d, J = 4.5Hz, 1H), yl)benzimidazol-5- 7.81-7.74 (m, 1H), 7.72 (d, J = 6.0 Hz,yl]-3-fluoropyridin-2- 1H), 7.50-7.43 (m, 2H), amine 6.83 (t, J = 5.8Hz, 1H), 2.71 (t, J = 7.5 Hz, 2H), 1.82-1.72 (m, 2H), 0.85 (t, J = 7.4Hz, 3H). 79 4-[3-(8- 497.2 1H NMR (400 MHz, DMSO-d6)chloroquinolin-4-yl)- δ 9.33 (d, J = 4.5 Hz, 1H), 8.28 (s,2-cyclopropyl-7-(4H- 1H), 8.23 (t, J = 1.5 Hz, 1H), 1,2,4-triazol-3-8.13-8.08 (m, 2H), 7.72 (d, J = 6.2 Hz, yl)benzimidazol-5- 1H), 7.62(dd, J = 8.5, 7.5 Hz, yl]-3-fluoropyridin-2- 1H), 7.39 (s, 1H), 7.36(dd, J = 8.5, amine 1.2 Hz, 1H), 6.86 (t, J = 6.0 Hz, 1H), 1.71-1.63 (m,1H), 1.53 (br s, 1H), 1.46 (br s, 1H), 1.07-0.97 (m, 1H), 0.97-0.87 (m,1H). 80 4-[3-(8- 471.2 1H NMR (400 MHz, DMSO-d6) chloroquinolin-4-yl)- δ9.33 (d, J = 4.5 Hz, 1H), 8.25 (t, 2-methyl-7-(4H- J = 1.5 Hz, 1H), 8.11(dd, J = 7.5, 1,2,4-triazol-3- 1.2 Hz, 1H), 8.07 (d, J = 4.5 Hz,yl)benzimidazol-5- 1H), 7.72 (d, J = 6.0 Hz, 1H), yl]-3-fluoropyridin-2-7.60 (dd, J = 8.5, 7.5 Hz, 1H), amine 7.41 (s, 1H), 7.37 (d, J = 8.4 Hz,1H), 6.80 (t, J = 5.8 Hz, 1H), 2.51 (s, 3H). 81 4-[2-cyclopropyl-3-499.2 1H NMR (400 MHz, DMSO-d6) (5,8- δ 9.30 (d, J = 4.5 Hz, 1H), 8.26(s, difluoroquinolin-4- 1H), 8.20 (d, J = 1.7 Hz, 1H), yl)-7-(4H-1,2,4-8.12 (d, J = 4.5 Hz, 1H), triazol-3- 7.81-7.74 (m, 1H), 7.73 (d, J = 6.1Hz, yl)benzimidazol-5- 1H), 7.51-7.44 (m, 2H), 6.86 (t,yl]-3-fluoropyridin-2- J = 5.9 Hz, 1H), 1.72 (td, J = 8.2, amine 4.2 Hz,1H), 1.50 (br s, 1H), 1.38 (br s, 1H), 1.02-0.89 (m, 1H). 82 4-[3-(5,8-487 2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4- δ 9.31 (d, J = 4.5Hz, 1H), 8.43 (s, yl)-2-methyl-7-(4H- 1H), 8.16 (t, J = 1.7 Hz, 1H),1,2,4-triazol-3- 8.10 (d, J = 4.5 Hz, 1H), 8.04 (d, J = 3.3 Hz,yl)benzimidazol-5- 1H), 7.79 (td, J = 9.5, 4.2 Hz, yl]-5-fluoro-N- 1H),7.53-7.43 (m, 2H), methylpyridin-2- 6.65 (d, J = 5.7 Hz, 1H), 2.76 (s,amine 3H), 2.51 (s, 3H). 83 4-[3-(8-chloro-5- 489.2 1H NMR (400 MHz,DMSO-d6) fluoroquinolin-4-yl)- δ 9.38 (d, J = 4.5 Hz, 1H), 8.42 (s,2-methyl-7-(4H- 1H), 8.25-8.21 (m, 1H), 1,2,4-triazol-3- 8.15-8.09 (m,2H), 7.73 (d, J = 6.0 Hz, yl)benzimidazol-5- 1H), 7.54 (s, 1H), 7.48(dd, J = 11.9, yl]-3-fluoropyridin-2- 8.6 Hz, 1H), 6.85 (t, J = 5.8 Hz,amine 1H), 2.50 (s, 3H). 84 4-[3-(8-chloro-5- 417.2 1H NMR (400 MHz,DMSO-d6) fluoroquinolin-4-yl)- δ 9.37 (d, J = 4.5 Hz, 1H), 8.36 (s,2-propyl-7-(4H- 1H), 8.20 (s, 1H), 8.15-8.08 (m, 1,2,4-triazol-3- 2H),7.72 (d, J = 6.0 Hz, 1H), yl)benzimidazol-5- 7.51-7.42 (m, 2H), 6.83 (t,J = 5.8 Hz, yl]-3-fluoropyridin-2- 1H), 2.71 (t, J = 7.6 Hz, amine 2H),1.82-1.73 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 85 4-[3-(8-chloro-5- 515.21H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- δ 9.37 (d, J = 4.5 Hz,1H), 8.26 (s, 2-cyclopropyl-7-(4H- 1H), 8.21 (s, 1H), 8.14-8.10 (m,1,2,4-triazol-3- 2H), 7.73 (d, J = 6.1 Hz, 1H), yl)benzimidazol-5-7.53-7.45 (m, 2H), 6.87 (t, J = 5.9 Hz, yl]-3-fluoropyridin-2- 1H),1.77-1.68 (m, 1H), amine 1.50 (br s, 1H), 1.37 (br s, 1H), 1.02-0.88 (m,1H). 86 3-fluoro-4-[3-(8- 455.2 1H NMR (400 MHz, DMSO-d6)fluoroquinolin-4-yl)- δ 9.27 (d, J = 4.5 Hz, 1H), 8.53 (s,2-methyl-7-(4H- 1H), 8.29 (t, J = 1.5 Hz, 1H), 1,2,4-triazol-3- 8.07 (d,J = 4.5 Hz, 1H), yl)benzimidazol-5- 7.80-7.73 (m, 2H), 7.62 (td, J =8.1, 5.0 Hz, yl]pyridin-2-amine 1H), 7.46 (t, J = 1.3 Hz, 1H), 7.26 (d,J = 8.4 Hz, 1H), 6.89 (t, J = 6.1 Hz, 1H), 2.55 (s, 3H). 873-fluoro-4-[3-(8- 483.2 1H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)-δ 9.26 (d, J = 4.5 Hz, 1H), 8.43 (s, 2-propyl-7-(4H- 1H), 8.25 (t, J =1.5 Hz, 1H), 1,2,4-triazol-3- 8.07 (d, J = 4.5 Hz, 1H),yl)benzimidazol-5- 7.79-7.72 (m, 2H), 7.61 (td, J = 8.2, 5.0 Hz,yl]pyridin-2-amine 1H), 7.39 (t, J = 1.3 Hz, 1H), 7.15 (d, J = 8.5 Hz,1H), 6.87 (t, J = 6.0 Hz, 1H), 2.73 (dd, J = 8.2, 6.8 Hz, 2H), 1.73 (qt,J = 8.6, 4.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H). 88 4-[2-cyclopropyl-3-481.2 1H NMR (400 MHz, DMSO-d6) (8-fluoroquinolin-4- δ 9.26 (d, J = 4.5Hz, 1H), 8.29 (s, yl)-7-(4H-1,2,4- 1H), 8.23 (t, J = 1.5 Hz, 1H),triazol-3- 8.08 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5- 7.79-7.71 (m,2H), 7.63 (td, J = 8.1, 5.0 Hz, yl]-3-fluoropyridin-2- 1H), 7.39 (t, J =1.3 Hz, 1H), amine 7.25-7.19 (m, 1H), 6.89 (t, J = 6.0 Hz, 1H), 1.67(td, J = 8.2, 4.3 Hz, 1H), 1.57-1.42 (m, 2H), 1.07-1.00 (m, 1H),0.99-0.87 (m, 1H). 89 4-[3-(8-chloro-3- 485.2 1H NMR (400 MHz, DMSO-d6)methylquinolin-4-yl)- δ 9.27 (d, J = 0.5 Hz, 1H), 8.43 (s,2-methyl-7-(4H- 1H), 8.25-8.23 (m, 1H), 1,2,4-triazol-3- 8.02 (dd, J =7.5, 1.2 Hz, 1H), 7.72 (d, yl)benzimidazol-5- J = 6.1 Hz, 1H), 7.55 (dd,J = 8.5, yl]-3-fluoropyridin-2- 7.5 Hz, 1H), 7.39 (s, 1H), amine 7.11(dd, J = 8.4, 1.2 Hz, 1H), 6.85 (t, J = 5.8 Hz, 1H), 2.41 (s, 3H), 2.20(s, 3H). 90 4-[3-(5,8- 469.2 1H NMR (400 MHz, DMSO-d6)difluoroquinolin-4- δ 9.33 (d, J = 4.5 Hz, 1H), yl)-2-methyl-7-(4H- 8.30(d, J = 1.7 Hz, 1H), 8.08 (d, J = 4.5 Hz, 1,2,4-triazol-3- 1H),7.84-7.75 (m, 1H), yl)benzimidazol-5- 7.64 (s, 1H), 7.60 (s, 2H),yl]-6-methylpyridin- 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2-amine 7.10(s, 1H), 7.06 (s, 1H), 2.45 (s, 3H), 2.39 (s, 3H). 913-chloro-4-[3-(5,8- 489.2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4-δ 9.30 (d, J = 4.5 Hz, 1H), 8.47 (s, yl)-2-methyl-7-(4H- 1H), 8.10 (d, J= 4.5 Hz, 1H), 1,2,4-triazol-3- 8.07 (d, J = 1.6 Hz, 1H), 7.90 (d, J =5.6 Hz, yl)benzimidazol-5- 1H), 7.78 (td, J = 9.4, yl]pyridin-2-amine4.2 Hz, 1H), 7.49 (ddd, J = 12.4, 8.9, 3.8 Hz, 1H), 7.41 (d, J = 1.6 Hz,1H), 6.70 (d, J = 5.6 Hz, 1H), 2.55 (s, 3H). 92 4-[3-(3-chloro-8- 489.21H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- δ 9.35 (s, 1H), 8.39 (s,1H), 2-methyl-7-(4H- 8.22 (t, J = 1.5 Hz, 1H), 7.79 (ddd, J = 10.7,1,2,4-triazol-3- 7.8, 1.2 Hz, 1H), 7.73 (d, J = 6.0 Hz,yl)benzimidazol-5- 1H), 7.67 (td, J = 8.2, 5.0 Hz,yl]-3-fluoropyridin-2- 1H), 7.51 (s, 1H), 7.13 (d, J = 8.4 Hz, amine2H), 6.83 (t, J = 5.9 Hz, 1H), 2.43 (s, 3H). 93 3-fluoro-4-[3-(5- 455.21H NMR (400 MHz, DMSO-d6) fluoroquinolin-4-yl)- δ 9.26 (d, J = 4.5 Hz,1H), 2-methyl-7-(4H- 8.44 (br s, 1H), 8.23 (t, J = 1.5 Hz,1,2,4-triazol-3- 1H), 8.15 (dd, J = 8.6, 1.0 Hz, yl)benzimidazol-5- 1H),7.98 (d, J = 4.6 Hz, 1H), yl]pyridin-2-amine 7.91 (td, J = 8.3, 5.7 Hz,1H), 7.74 (d, J = 6.0 Hz, 1H), 7.51-7.43 (m, 2H), 6.87 (t, J = 5.9 Hz,1H), 2.51 (s, 3H). 94 4-[2-ethyl-3-(5- 469.2 1H NMR (400 MHz, DMSO-d6)fluoroquinolin-4-yl)- δ 9.26 (d, J = 4.5 Hz, 1H), 8.40 (s,7-(4H-1,2,4-triazol-3- 1H), 8.23 (t, J = 1.5 Hz, 1H), yl)benzimidazol-5-8.17-8.13 (m, 1H), 7.99 (d, J = 4.5 Hz, yl]-3-fluoropyridin-2- 1H), 7.90(ddd, J = 8.6, 7.9, amine 5.7 Hz, 1H), 7.75 (d, J = 6.3 Hz, 1H),7.50-7.42 (m, 2H), 6.92 (t, J = 6.1 Hz, 1H), 2.75 (qd, J = 7.7, 4.7 Hz,2H), 1.27 (t, J = 7.5 Hz, 3H). 95 4-[3-(5,8- 487.2 1H NMR (400 MHz,DMSO-d6) difluoroquinolin-4- δ 9.30 (d, J = 4.5 Hz, 1H), 8.38 (s,yl)-2-ethyl-7-(4H- 1H), 8.22 (s, 1H), 8.10 (d, J = 4.5 Hz,1,2,4-triazol-3- 1H), 7.83-7.71 (m, 2H), yl)benzimidazol-5- 7.51 (t, J =1.2 Hz, 1H), yl]-3-fluoropyridin-2- 7.46 (ddd, J = 12.4, 8.8, 3.8 Hz,1H), amine 6.89 (t, J = 6.0 Hz, 1H), 2.81-2.68 (m, 2H), 1.27 (t, J = 7.5Hz, 3H). 96 4-[2- 513.2 1H NMR (400 MHz, DMSO-d6) (cyclopropylmethyl)- δ9.29 (d, J = 4.5 Hz, 1H), 3-(5,8- 8.37 (br s, 1H), 8.21 (d, J = 1.6 Hz,difluoroquinolin-4- 1H), 8.09 (d, J = 4.5 Hz, 1H), yl)-7-(4H-1,2,4-7.81-7.71 (m, 2H), triazol-3- 7.51-7.41 (m, 2H), 6.84 (t, J = 5.8 Hz,1H), yl)benzimidazol-5- 2.73 (dd, J = 6.9, 4.1 Hz, 2H),yl]-3-fluoropyridin-2- 1.07 (br s, 1H), 0.40-0.22 (m, amine 2H),0.12-−0.14 (m, 2H). 97 4-[3-(5,8- 487.2 1H NMR (400 MHz, DMSO-d6)difluoroquinolin-4- δ 9.31 (d, J = 4.5 Hz, 1H), 8.22 (t,yl)-2-methyl-7-(5- J = 1.6 Hz, 1H), 8.09 (d, J = 4.5 Hz,methyl-4H-1,2,4- 1H), 7.83-7.76 (m, 1H), triazol-3- 7.74 (d, J = 6.0 Hz,1H), 7.53 (d, J = 1.5 Hz, yl)benzimidazol-5- 1H), 7.48 (ddd, J = 12.4,yl-]3-fluoropyridin-2- 8.8, 3.8 Hz, 1H), 6.85 (t, J = 5.9 Hz, amine 1H),2.52 (s, 3H), 2.47 (s, 3H). 98 4-[3-(8-chloro-5- 503.2 1H NMR (400 MHz,DMSO-d6) fluoroquinolin-4-yl)- δ 9.39 (d, J = 4.5 Hz, 1H), 8.25 (t,2-methyl-7-(5- J = 1.6 Hz, 1H), 8.16-8.10 (m, methyl-4H-1,2,4- 2H), 7.75(d, J = 6.2 Hz, 1H), triazol-3- 7.59 (dd, J = 1.7, 0.9 Hz, 1H),yl)benzimidazol-5- 7.49 (dd, J = 11.9, 8.6 Hz, 1H),yl]-3-fluoropyridin-2- 6.89 (t, J = 6.0 Hz, 1H), 2.54 (s, amine 3H),2.49 (s, 3H). 99 4-[3-(5-chloro-8- 489.1 1H NMR (400 MHz, DMSO-d6)fluoroquinolin-4-yl)- δ 9.27 (d, J = 4.4 Hz, 1H), 8.15 (s,2-methyl-7-(4H- 1H), 8.00 (d, J = 4.8 Hz, 1H), 1,2,4-triazol-3-7.80-7.74 (m, 2H), 7.68 (d, J = 5.2 Hz, yl)benzimidazol-5- 1H), 7.11 (s,1H), 6.59 (t, yl]-3-fluoropyridin-2- J = 5.3 Hz, 1H), 6.16 (s, 2H),amine 2.36 (s, 3H). 100 4-[3-(5,8- 491.1 1H NMR (400 MHz, DMSO-d6)difluoroquinolin-4- δ 9.30 (d, J = 4.5 Hz, 1H), 8.47 (s,yl)-2-methyl-7-(4H- 1H), 8.10 (d, J = 4.6 Hz, 1H), 1,2,4-triazol-3- 8.06(d, J = 1.4 Hz, 1H), 7.87 (t, J = 0.6 Hz, yl)benzimidazol-5- 1H),7.82-7.75 (m, yl]-3,5- 1H), 7.52-7.44 (m, 2H), 2.55 (s,difluoropyridin-2- 3H). amine 101 4-[3-(5,8- 469.2 1H NMR (400 MHz,DMSO-d6) difluoroquinolin-4- δ 9.28 (d, J = 4.5 Hz, 1H),yl)-2-methyl-7-(4H- 8.06 (d, J = 4.5 Hz, 1H), 7.88 (d, J = 1.6 Hz,1,2,4-triazol-3- 1H), 7.84-7.74 (m, 4H), yl)benzimidazol-5- 7.47 (ddd, J= 12.3, 8.8, 3.9 Hz, yl]-3-methylpyridin- 1H), 7.29 (s, 1H), 6.83 (d, J= 6.6 Hz, 2-amine 1H), 1.99 (s, 3H). 102 4-[3-(5,8- 459.1 1H NMR (400MHz, DMSO-d6) difluoroquinolin-4- δ 9.24 (d, J = 4.6 Hz, 1H), 8.91 (s,yl)-7-(4H-1,2,4- 1H), 8.21 (s, 1H), 8.06 (d, J = 4.6 Hz, triazol-3- 1H),7.78 (ddd, J = 10.1, 8.8, yl)benzimidazol-5- 4.2 Hz, 1H), 7.73 (d, J =5.3 Hz, yl]-3-fluoropyridin-2- 1H), 7.66 (s, 1H), 7.48 (ddd, J = 12.4,amine 8.8, 3.9 Hz, 1H), 6.68 (t, J = 5.2 Hz, 1H), 6.30 (s, 2H). 1604-(1-(5,7- 473.2 1H NMR (400 MHz, DMSO-d6) difluoroquinolin-4- δ 9.28(d, J = 4.6 Hz, 1H), 8.41 (s, yl)-2-methyl-4-(4H- 1H), 8.22 (t, J = 1.6Hz, 1H), 1,2,4-triazol-3-yl)- 8.01-7.94 (m, 2H), 7.74 (d, J = 6.0 Hz,1H- 1H), 7.66 (ddd, J = 12.0, 9.2, benzo[d]imidazol-6- 2.5 Hz, 1H), 7.49(s, 1H), 6.85 (t, yl)-3-fluoropyridin-2- J = 5.8 Hz, 1H), 2.51 (s, 3H).amine 161 4-(1-(5,8- 505.1 1H NMR (400 MHz, DMSO-d6) dichloroquinolin-4-δ 9.38 (d, J = 4.4 Hz, 1H), 8.45 (s, yl)-2-methyl-4-(4H- 1H), 8.25 (t, J= 1.6 Hz, 1H), 1,2,4-triazol-3-yl)- 8.12 (d, J = 8.3 Hz, 1H), 8.09 (d, J= 4.4 Hz, 1H- 1H), 7.78 (d, J = 8.3 Hz, benzo[d]imidazol-6- 1H), 7.74(d, J = 6.2 Hz, 1H), yl)-3-fluoropyridin-2- 7.53-7.49 (m, 1H), 6.88 (t,J = 6.0 Hz, amine 1H), 2.48 (s, 3H).

A. Preparation of4-(6-(2,3-difluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2-(piperazin-1-yl)quinoline

To a solution of tert-butyl4-(4-(6-(2,3-difluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate(41 mg, 0.07 mmol) in DCM (1.0 mL) was added TFA (0.2 mL). The mixturewas then stirred for 1 hour. After concentration under reduced pressure,the resultant was purified by HPLC eluting with 5-95% water/acetonitrile(0.1% v/v trifluoroacetic acid). The appropriate fractions were pooledand lyophilized to afford4-(6-(2,3-difluoropyridin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2-(piperazin-1-yl)quinolineas a 2,2,2-trifluoroacetic acid salt. ES/MS m/z=510.2 (M+H)+ (Example164)

The following compounds were synthesized using a similar method:

Example Name MS NMR 162 3-fluoro-4-(1-(2- 507.3 1H NMR (400 MHz,DMSO-d6) (piperazin-1- δ 8.96 (s, 1H), 8.91 (s, 0H), 8.37yl)quinolin-4-yl)-4- (s, 1H), 8.27 (t, J = 1.5 Hz, 1H),(4H-1,2,4-triazol-3- 7.82-7.73 (m, 3H), 7.70 (ddd, J = yl)-1H- 8.4, 5.7,2.7 Hz, 1H), 7.59 (d, J = benzo[d]imidazol-6- 1.6 Hz, 1H), 7.34-7.26 (m,yl)pyridin-2-amine 2H), 6.85 (t, J = 5.7 Hz, 1H), 3.98 (s, 4H), 3.24 (s,4H). 163 3-fluoro-4-(1-(2- 440.2 1H NMR (400 MHz, DMSO-d6) (piperazin-1-δ 8.92 (s, 2H), 8.75 (s, 1H), 8.01 yl)quinolin-4-yl)-1H- (dd, J = 8.5,0.6 Hz, 1H), 7.81- benzo[d]imidazol-6- 7.74 (m, 2H), 7.72-7.65 (m,yl)pyridin-2-amine 2H), 7.63 (dt, J = 8.5, 1.6 Hz, 1H), 7.49 (s, 1H),7.32-7.22 (m, 2H), 6.85 (t, J = 5.9 Hz, 1H), 3.97 (s, 4H), 3.23 (s, 4H).164 4-(6-(2,3- 510.2 1H NMR (400 MHz, DMSO-d6) difluoropyridin-4-yl)- δ8.96 (s, 1H), 8.85 (s, 3H), 8.37 4-(4H-1,2,4-triazol-3- (s, 1H), 8.29(t, J = 1.6 Hz, 1H), yl)-1H- 8.05 (dd, J = 5.1, 1.1 Hz, 1H),benzo[d]imidazol-1- 7.79 (dt, J = 8.5, 1.0 Hz, 1H), yl)-2-(piperazin-1-7.75 (s, 1H), 7.73-7.67 (m, 2H), yl)quinoline 7.61 (t, J = 5.1 Hz, 1H),7.32- 7.28 (m, 2H), 3.98 (s, 4H), 3.24 (s, 4H). 165 4-(6-(2,3- 443.2 1HNMR (400 MHz, DMSO-d6) difluoropyridin-4-yl)- δ 8.91 (s, 2H), 8.77 (d, J= 0.4 1H- Hz, 1H), 8.05-8.01 (m, 2H), benzo[d]imidazol-1- 7.80-7.76 (m,1H), 7.73-7.64 (m, yl)-2-(piperazin-1- 4H), 7.60-7.57 (m, 1H), 7.55 (t,yl)quinoline J = 5.1 Hz, 1H), 7.33-7.24 (m, 2H), 3.97 (s, 4H), 3.23 (s,4H). 166 4-(1-(2-(1H-pyrazol- 481.2 1H NMR (400 MHz, DMSO-d6)4-yl)quinolin-4-yl)-4- δ 9.05 (s, 1H), 8.72 (dd, J = 5.3,(4H-1,2,4-triazol-3- 0.7 Hz, 1H), 8.49-8.43 (m, 4H), yl)-1H- 8.33 (s,1H), 8.18-8.15 (m, 1H), benzo[d]imidazol-6- 8.11 (dd, J = 5.3, 1.9 Hz,1H), yl)picolinonitrile 8.02 (d, J = 1.7 Hz, 1H), 7.87- 7.81 (m, 1H),7.53 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H). 1674-(1-(2-(piperazin-1- 499.2 1H NMR (400 MHz, DMSO-d6)yl)quinolin-4-yl)-4- δ 8.93 (s, 1H), 8.86 (s, 2H), 8.74(4H-1,2,4-triazol-3- (dd, J = 5.2, 0.8 Hz, 1H), 8.47- yl)-1H- 8.42 (m,2H), 8.38 (s, 1H), 8.11 benzo[d]imidazol-6- (dd, J = 5.3, 1.9 Hz, 1H),7.99 (d, yl)picolinonitrile J = 1.8 Hz, 1H), 7.81 (dt, J = 8.5, 0.9 Hz,1H), 7.75 (s, 1H), 7.70 (ddd, J = 8.4, 6.4, 1.9 Hz, 1H), 7.34-7.23 (m,2H), 3.99 (s, 4H), 3.25 (s, 4H).

Separation of Atropisomers of Compounds of Formula (IM) A. Separation ofthe Atropisomers of4-(1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-amine

The atropisomers of Example 48 were separated on OD-H SFC 5 μM 21×250 mmcolumn in 30% EtOH/CO₂ at 60 mL/min to give the two single atropisomersof4-(1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)pyridin-2-amine(Example 103 and Example 104).

The following compounds were prepared using a similar procedure:

Separation Peak Ex- Name method # ample MS NMR 4-(1-(5,8- OD-H SFC1^(st) 103 455.2 1H NMR difluoroquinolin- 5 uM e- (400 MHz,4-yl)-2-methyl- 21 × luting DMSO-d6) δ 9.32 4-(4H-1,2,4- 250 mm peak (d,J = 4.5 Hz, 1H), triazol-3-yl)- column in 8.30 (d, J = 1.3 Hz, 1H- 30%1H), 8.07 (d, J = 4.7 benzo[d] MeOH/ Hz, 1H), 7.89 (d, J = imidazol- CO26.8 Hz, 1H), 7.87- 6-yl)pyridin-2- at 60 7.74 (m, 4H), 7.69 amine mL/min(s, 1H), 7.52-7.36 (m, 1H), 7.26-7.19 (m, 2H), 2.45 (s, 3H). 2^(nd) 104455.2 1H NMR e- (400 MHz, luting DMSO-d6) δ 9.32 peak (d, J = 4.5 Hz,1H), 8.30 (d, J = 1.3 Hz, 1H), 8.07 (d, J = 4.7 Hz, 1H), 7.89 (d, J =6.8 Hz, 1H), 7.87- 7.74 (m, 4H), 7.69 (s, 1H), 7.52-7.36 (m, 1H),7.26-7.19 (m, 2H), 2.45 (s, 3H).

Separation of atropisomers: The atropisomers of were separated on OD-HSFC 5 uM 21×250 mm column. The conditions for the separation ofatropisomers and characterization data are provided in the table below:

Separa- tion Peak Ex- Name method # ample MS NMR 4-[3-(5,8- OD-H 1^(st)105 473.2 ¹H NMR (400 MHz, difluoroquinolin- SFC e- DMSO-d6) δ 9.314-yl)-2- 5 uM luting (d, J = 4.5 Hz, 1H), methyl-7- 21 × peak 8.41 (hrs, 1H), 8.22 (4H-1,2,4- 250 mm (s, 1H), 8.09 (d, J = triazol-3-yl)column 4.5 Hz, 1H), 7.78 benzimidazol- in 30% (td, J = 9.5, 4.2 Hz,5-yl]-3- MeOH/ 1H), 7.74 (dd, J = fluoropyridin- CO2 6.2, 0.9 Hz, 1H),2-amine at 60 7.52 (s, 1H), 7.47 mL/min (ddd, J = 12.3, 8.8, 3.8 Hz,1H), 6.84 (br s, 1H), 2.51 (s, 3H). 2^(nd) 106 473.2 ¹H NMR (400 MHz, e-DMSO-d6) δ 9.31 luting (d, J = 4.5 Hz, 1H), peak 8.41 (br s, 1H), 8.22(s, 1H), 8.09 (d, J = 4.5 Hz, 1H), 7.78 (td, J = 9.5, 4.2 Hz, 1H), 7.74(dd, J = 6.2, 0.9 Hz, 1H), 7.52 (s, 1H), 7.47 (ddd, J = 12.3, 8.8, 3.8Hz, 1H), 6.84 (br s, 1H), 2.51 (s, 3H). 4-[3-(3-chloro-8- Chiralpak1^(st) 107 489.2 ¹H NMR (400 MHz, fluoroquinolin-4- OD-H e- DMSO-d6) δ9.35 yl)-2-methyl-7- 150 × luting (s, 1H), 8.39 (s, 1H),(4H-1,2,4-triazol- 4.6 mm peak 8.22 (t, J = 1.5 Hz, 3-yl) column in 1H),7.79 (ddd, J = benzimidazol- 30% 10.7, 7.8, 1.2 Hz, 5-yl]-3- IPA/ 1H),7.73 (d, J = 6.0 fluoropyridin- Heptane Hz, 1H), 7.67 (td, J = 2-amineat 7 mL/ 8.2, 5.0 Hz, 1H), min 7.51 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H),6.83 (t, J = 5.9 Hz, 1H), 2.43 (s, 3H). 2^(nd) 108 489.2 ¹H NMR (400MHz, e- DMSO-d6) δ 9.35 luting (s, 1H), 8.39 (s, 1H), peak 8.22 (t, J =1.5 Hz, 1H), 7.79 (ddd, J = 10.7, 7.8, 1.2 Hz, 1H), 7.73 (d, J = 6.0 Hz,1H), 7.67 (td, J = 8.2, 5.0 Hz, 1H), 7.51 (s, 1H), 7.13 (d, J = 8.4 Hz,2H), 6.83 (t, J = 5.9 Hz, 1H), 2.43 (s, 3H). 4-[3-(5,8- OD-H 1^(st) 109487.2 ¹H NMR (400 MHz, difluoroquinolin- SFC e- DMSO-d6) δ 9.304-yl)-2-ethyl- 5 uM luting (d, J = 4.5 Hz, 1H), 7-(4H- 21 × peak 8.38(s, 1H), 8.22 (s, 1,2,4-triazol-3- 250 mm 1H), 8.10 (d, J = 4.5yl)benzimidazol- column in Hz, 1H), 7.83-7.71 5-yl]-3- 30% (m, 2H), 7.51(t, J = fluoropyridin- MeOH/ 1.2 Hz, 1H), 7.46 2-amine CO2 (ddd, J =12.4, 8.8, at 60 mL/ 3.8 Hz, 1H), 6.89 (t, min J = 6.0 Hz, 1H), 2.81-2.68 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). 2^(nd) 110 487.2 ¹H NMR (400MHz, e- DMSO-d6) δ 9.30 luting (d, J = 4.5 Hz, 1H), peak 8.38 (s, 1H),8.22 (s, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.83-7.71 (m, 2H), 7.51 (t, J =1.2 Hz, 1H), 7.46 (ddd, J = 12.4, 8.8, 3.8 Hz, 1H), 6.89 (t, J = 6.0 Hz,1H), 2.81- 2.68 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). 4-[3-(8- OD-H 1^(st)111 503.2 ¹H NMR (400 MHz, chloro-5- SFC e- DMSO-d6) δ 9.39fluoroquinolin- 5 uM luting (d, J = 4.5 Hz, 1H), 4-yl)-2- 21 × peak 8.25(t, J = 1.6 Hz, methyl-7-(5- 250 mm 1H), 8.16-8.10 (m, methyl-4H- columnin 2H), 7.75 (d, J = 6.2 1,2,4-triazol-3- 30% Hz, 1H), 7.59 (dd,yl)benzimidazol- MeOH/ J = 1.7, 0.9 Hz, 1H), 5-yl]-3- CO2 7.49 (dd, J =11.9, fluoropyridin- at 60 8.6 Hz, 1H), 6.89 (t, 2-amine mL/min J = 6.0Hz, 1H), 2.54 (s, 3H), 2.49 (s, 3H). 2^(nd) 112 503.2 ¹H NMR (400 MHz,e- DMSO-d6) δ 9.39 luting (d, J = 4.5 Hz, 1H), peak 8.25 (t, J = 1.6 Hz,1H), 8.16-8.10 (m, 2H), 7.75 (d, J = 6.2 Hz, 1H), 7.59 (dd, J = 1.7, 0.9Hz, 1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H), 6.89 (t, J = 6.0 Hz, 1H), 2.54(s, 3H), 2.49 (s, 3H). 4-[3-(5,8- OJ-H 1^(st) 113 465.1 ¹H NMR (400 MHz,difluoroquinolin- SFC e- DMSO-d6) δ 9.34 4-yl)-2-methyl- 5 uM luting (d,J = 4.5 Hz, 1H), 7-(4H-1,2,4- 21 × peak 8.71 (dd, J = 5.3, 0.8triazol-3-yl) 250 mm Hz, 1H), 8.50 (s, benzimidazol- column in 1H), 8.43(d, J = 1.7 5-yl]pyridine- 30% Hz, 1H), 8.39 (dd, 2-carbonitrile EtOH/ J= 2.0, 0.8 Hz, 1H), CO2 at 8.11-8.07 (m, 2H), 60 mL/ 7.87 (d, J = 1.7Hz, min 1H), 7.79 (ddd, J = 10.1, 8.8, 4.3 Hz, 1H), 7.48 (ddd, J = 12.3,8.8, 3.8 Hz, 1H), 2.52 (s, 3H). 2^(nd) 114 465.1 ¹H NMR (400 MHz, e-DMSO-d6) δ 9.34 luting (d, J = 4.5 Hz, 1H), peak 8.71 (dd, J = 5.3, 0.8Hz, 1H), 8.50 (s, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.39 (dd, J = 2.0, 0.8Hz, 1H), 8.11-8.07 (m, 2H), 7.87 (d, J = 1.7 Hz, 1H), 7.79 (ddd, J =10.1, 8.8, 4.3 Hz, 1H), 7.48 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.52 (s,3H). 4-(1-(5,7- OJ-H 1^(st) 115 465.2 1H NMR (400 MHz, difluoroquinolin-SFC e- DMSO-d6) δ 9.31 4-yl)-2-methyl-4- 5 uM luting (d, J = 4.6 Hz,1H), (4H- 21 × peak 8.72 (dd, J = 5.3, 0.8 1,2,4-triazol- 250 mm Hz,1H), 8.55-8.49 3-yl)-1H- column in (m, 1H), 8.43 (d, J = benzo[d] 15%1.7 Hz, 1H), 8.40 imidazol-6-yl) EtOH/ (dd, J = 1.9, 0.8 Hz,picolinonitrile CO2 at 1H), 8.09 (dd, J = 60 mL/ 5.3, 2.0 Hz, 1H), min8.00 (ddd, J = 9.7, 2.5, 1.3 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.86 (d,J = 1.7 Hz, 1H), 7.66 (ddd, J = 12.1, 9.3, 2.5 Hz, 1H), 2.52 (t, J = 0.5Hz, 3H). 2^(nd) 116 465.1 1H NMR (400 MHz, e- DMSO-d6) δ 9.31 luting (d,J = 4.6 Hz, 1H), peak 8.72 (dd, J = 5.3, 0.8 Hz, 1H), 8.55-8.49 (m, 1H),8.43 (d, J = 1.7 Hz, 1H), 8.40 (dd, J = 1.9, 0.8 Hz, 1H), 8.09 (dd, J =5.3, 2.0 Hz, 1H), 8.00 (ddd, J = 9.7, 2.5, 1.3 Hz, 1H), 7.97 (d, J = 4.6Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.66 (ddd, J = 12.1, 9.3, 2.5 Hz,1H), 2.52 (t, J = 0.5 Hz, 3H). 4-(1-(5,7- AD-H 1^(st) 117 473.2 1H NMR(400 MHz, difluoroquinolin- SFC e- DMSO-d6) δ 9.28 4-yl)-2-methyl- 5 uMluting (d, J = 4.6 Hz, 1H), 4-(4H-1,2,4- 21 × peak 8.41 (s, 1H), 8.22(t, triazol- 250 mm J = 1.6 Hz, 1H), 8.01- 3-yl)-1H- column in 7.94 (m,2H), 7.74 benzo[d] 35% (d, J = 6.0 Hz, 1H), imidazol- MeOH/ 7.66 (ddd, J= 12.0, fluoropyridin- CO2 9.2, 2.5 Hz, 1H), 2-amine at 60 mL/ 7.49 (s,1H), 6.85 (t, min J = 5.8 Hz, 1H), 2.51 (s, 3H). 2^(nd) 118 473.2 1H NMR(400 MHz, e- DMSO-d6) δ 9.28 luting (d, J = 4.6 Hz, 1H), peak 8.41 (s,1H), 8.22 (t, J = 1.6 Hz, 1H), 8.01- 7.94 (m, 2H), 7.74 (d, J = 6.0 Hz,1H), 7.66 (ddd, J = 12.0, 9.2, 2.5 Hz, 1H), 7.49 (s, 1H), 6.85 (t, J =5.8 Hz, 1H), 2.51 (s, 3H). 4-(1-(5,8- AD-H 1^(st) 119 505.1 1H NMR (400MHz, dichloroquinolin- SFC e- DMSO-d6) δ 9.38 4-yl)-2-methyl- 5 uMluting (d, J = 4.4 Hz, 1H), 4-(4H-1,2,4- 21 × peak 8.45 (s, 1H), 8.25(t, triazol-3-yl)-1H- 250 mm J = 1.6 Hz, 1H), 8.12 benzo[d] column in(d, J = 8.3 Hz, 1H), imidazol- 35% 8.09 (d, J = 4.4 Hz, 6-yl)-3- MeOH/1H), 7.78 (d, J = 8.3 fluoropyridin- CO2 Hz, 1H), 7.74 (d, J = 2-amineat 60 mL/ 6.2 Hz, 1H), 7.53- min 7.49 (m, 1H), 6.88 (t, J = 6.0 Hz, 1H),2.48 (s, 3H). 2^(nd) 120 505.1 1H NMR (400 MHz, e- DMSO-d6) δ 9.38luting (d, J = 4.4 Hz, 1H), peak 8.45 (s, 1H), 8.25 (t, J = 1.6 Hz, 1H),8.12 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 4.4 Hz, 1H), 7.78 (d, J = 8.3 Hz,1H), 7.74 (d, J = 6.2 Hz, 1H), 7.53- 7.49 (m, 1H), 6.88 (t, J = 6.0 Hz,1H), 2.48 (s, 3H). 4-(1-(5,8- OJ-H 1^(st) 121 497.2 1H NMR (400 MHz,dichloroquinolin- SFC e- DMSO-d6) δ 9.42 4-yl)-2-methyl- 5 uM luting (d,J = 4.4 Hz, 1H), 4-(4H-1,2,4- 21 × peak 8.71 (dd, J = 5.3, 0.8triazol-3-yl)-1H- 250 mm Hz, 1H), 8.55 (s, benzo[d] column 1H), 8.46 (d,J = 1.7 imidazol-6-yl) in 30% Hz, 1H), 8.40 (dd, picolinonitrile EtOH/ J= 2.0, 0.8 Hz, 1H), CO2 at 8.15-8.07 (m, 3H), 60 mL/ 7.86 (d, J = 1.7Hz, min 1H), 7.78 (d, J = 8.3 Hz, 1H), 2.50 (s, 3H). 2^(nd) 122 497.1 1HNMR (400 MHz, e- DMSO-d6) δ 9.42 luting (d, J = 4.4 Hz, 1H), peak 8.71(dd, J = 5.3, 0.8 Hz, 1H), 8.55 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.40(dd, J = 2.0, 0.8 Hz, 1H), 8.15-8.07 (m, 3H), 7.86 (d, J = 1.7 Hz, 1H),7.78 (d, J = 8.3 Hz, 1H), 2.50 (s, 3H). 4-(1-(5-chloro-8- OJ-H 1^(st)123 481.1 1H NMR (400 MHz, fluoroquinolin-4- SFC e- DMSO-d6) δ 9.35yl)-2-methyl-4- 5 uM luting (d, J = 4.4 Hz, 1H), (4H-1,2,4- 21 × peak8.71 (dd, J = 5.3, 0.8 triazol-3-yl)-1H- 250 mm Hz, 1H), 8.51 (s,benzo[d] column in 1H), 8.45 (d, J = 1.8 imidazol-6-yl) 30% Hz, 1H),8.40 (dd, picolinonitrile EtOH/ J = 1.9, 0.8 Hz, 1H), CO2 at 8.12-8.07(m, 2H), 60 mL/ 7.83 (d, J = 1.8 Hz, min 1H), 7.81 (d, J = 1.4 Hz, 1H),7.80 (s, 1H), 2.48 (s, 3H). 2^(nd) 124 481.1 1H NMR (400 MHz, e-DMSO-d6) δ 9.35 luting (d, J = 4.4 Hz, 1H), peak 8.71 (dd, J = 5.3, 0.8Hz, 1H), 8.51 (s, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.40 (dd, J = 1.9, 0.8Hz, 1H), 8.12-8.07 (m, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 1.4Hz, 1H), 7.80 (s, 1H), 2.48 (s, 3H). 4-(1-(5- OJ-H 1^(st) 125 463.1 1HNMR (400 MHz, chloroquinolin- SFC e- DMSO-d6) δ 9.27 4-yl)-2-methyl- 5uM luting (d, J = 4.6 Hz, 1H), 4-(4H-1,2,4- 21 × peak 8.70 (dd, J = 5.3,0.8 triazol-3-yl)- 250 mm Hz, 1H), 8.40 (d, J = 1H-benzo[d] column in1.8 Hz, 1H), 8.38 imidazol-6-yl) 30% (dd, J = 2.0, 0.8 Hz,picolinonitrile EtOH/ 1H), 8.37-8.35 (m, CO2 at 1H), 8.06 (dd, J = 60mL/ 5.3, 1.9 Hz, 1H), min 7.97 (d, J = 4.6 Hz, 1H), 7.73 (d, J = 1.8 Hz,1H), 7.65 (dd, J = 9.0, 2.2 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 2.47 (s,3H). 2^(nd) 126 463.1 1H NMR (400 MHz, e- DMSO-d6) δ 9.27 luting (d, J =4.6 Hz, 1H), peak 8.70 (dd, J = 5.3, 0.8 Hz, 1H), 8.40 (d, J = 1.8 Hz,1H), 8.38 (dd, J = 2.0, 0.8 Hz, 1H), 8.37-8.35 (m, 1H), 8.06 (dd, J =5.3, 1.9 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H),7.65 (dd, J = 9.0, 2.2 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 2.47 (s, 3H).4-(1-(8- OJ-H 1^(st) 127 447.2 1H NMR (400 MHz, fluoroquinolin- SFC e-DMSO-d6) δ 9.30 4-yl)-2-methyl- 5 uM luting (d, J = 4.5 Hz, 1H),4-(4H-1,2,4- 21 × peak 8.71 (dd, J = 5.3, 0.8 triazol-3-yl)-1H- 250 mmHz, 1H), 8.58 (s, benzo[d] column 1H), 8.48 (d, J = 1.7 imidazol-6-yl)in 30% Hz, 1H), 8.39 (dd, picolinonitrile EtOH/ J = 2.0, 0.8 Hz, 1H),CO2 at 8.10-8.04 (m, 2H), 60 mL/ 7.81 (d, J = 1.7 Hz, min 1H), 7.76(ddd, J = 10.8, 7.8, 1.2 Hz, 1H), 7.61 (td, J = 8.1, 5.0 Hz, 1H),7.32-7.24 (m, 1H), 2.54 (s, 3H). 2^(nd) 128 447.1 1H NMR (400 MHz, e-DMSO-d6) δ 9.30 luting (d, J = 4.5 Hz, 1H), peak 8.71 (dd, J = 5.3, 0.8Hz, 1H), 8.58 (s, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.39 (dd, J = 2.0, 0.8Hz, 1H), 8.10-8.04 (m, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.76 (ddd, J =10.8, 7.8, 1.2 Hz, 1H), 7.61 (td, J = 8.1, 5.0 Hz, 1H), 7.32-7.24 (m,1H), 2.54 (s, 3H). 4-(1-(8- OJ-H 1^(st) 129 463.1 1H NMR (400 MHz,chloroquinolin- SFC e- DMSO-d6) δ 9.36 4-yl)-2-methyl- 5 uM luting (d, J= 4.5 Hz, 1H), 4-(4H-1,2,4- 21 × peak 8.71 (dd, J = 5.3, 0.8triazol-3-yl)- 250 mm Hz, 1H), 8.58 (s, 1H-benzo[d] column in 1H), 8.48(d, J = 1.7 imidazol-6-yl) 30% Hz, 1H), 8.38 (dd, picolinonitrile EtOH/J = 2.0, 0.8 Hz, 1H), CO2 at 8.11 (dd, J = 7.5, 1.2 60 mL/ Hz, 1H),8.10-8.05 min (m, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.5, 7.5Hz, 1H), 7.43 (dd, J = 8.5, 1.2 Hz, 1H), 2.53 (s, 3H). 2^(nd) 130 463.11H NMR (400 MHz, e- DMSO-d6) δ 9.36 luting (d, J = 4.5 Hz, 1H), peak8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.58 (s, 1H), 8.48 (d, J = 1.7 Hz, 1H),8.38 (dd, J = 2.0, 0.8 Hz, 1H), 8.11 (dd, J = 7.5, 1.2 Hz, 1H),8.10-8.05 (m, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.5, 7.5 Hz,1H), 7.43 (dd, J = 8.5, 1.2 Hz, 1H), 2.53 (s, 3H). 4-(1-(5- OJ-H 1^(st)131 447.1 1H NMR (400 MHz, fluoroquinolin- SFC e- DMSO-d6) δ 9.304-yl)-2-methyl- 5 uM luting (d, J = 4.5 Hz, 1H), 4-(4H-1,2,4- 21 × peak8.71 (dd, J = 5.3, 0.8 triazol-3-yl)- 250 mm Hz, 1H), 8.57 (s,1H-benzo[d] column in 1H), 8.46 (d, J = 1.7 imidazol-6-yl) 30% Hz, 1H),8.41 (dd, picolinonitrile EtOH/ J = 2.0, 0.8 Hz, 1H), CO2 at 8.19-8.15(m, 1H), 60 mL/ 8.09 (dd, J = 5.3, 1.9 min Hz, 1H), 8.00 (d, J = 4.6 Hz,1H), 7.95- 7.87 (m, 2H), 7.48 (ddd, J = 12.4, 7.9, 1.0 Hz, 1H), 2.53 (s,3H). 2^(nd) 132 447.2 1H NMR (400 MHz, e- DMSO-d6) δ 9.30 luting (d, J =4.5 Hz, 1H), peak 8.71 (dd, J = 5.3, 0.8 Hz, 1H), 8.57 (s, 1H), 8.46 (d,J = 1.7 Hz, 1H), 8.41 (dd, J = 2.0, 0.8 Hz, 1H), 8.19-8.15 (m, 1H), 8.09(dd, J = 5.3, 1.9 Hz, 1H), 8.00 (d, J = 4.6 Hz, 1H), 7.95- 7.87 (m, 2H),7.48 (ddd, J = 12.4, 7.9, 1.0 Hz, 1H), 2.53 (s, 3H). 5,8-difluoro-4-OJ-H 1^(st) 133 458.1 1H NMR (400 MHz, (6-(2- SFC e- DMSO-d6) δ 9.33fluoropyridin- 5 uM luting (d, J = 4.5 Hz, 1H), 4-yl)-2-methyl- 21 ×peak 8.33 (s, 1H), 8.23 (d, 4-(4H-1,2,4- 250 mm J = 5.4 Hz, 2H), 8.08triazol-3-yl)-1H- column in (d, J = 4.5 Hz, 1H), benzo[d] 30% 7.85-7.74(m, 3H), imidazol-1-yl) EtOH/ 7.72 (dt, J = 5.5, 1.8 quinoline CO2 atHz, 1H), 7.52 (s, 60 mL/ 1H), 7.47 (ddd, J = min 12.4, 8.8, 3.9 Hz, 1H),2.46 (s, 3H). 2^(nd) 134 458.1 1H NMR (400 MHz, e- DMSO-d6) δ 9.33luting (d, J = 4.5 Hz, 1H), peak 8.39 (s, 1H), 8.35 (d, J = 1.7 Hz, 1H),8.23 (d, J = 5.4 Hz, 1H), 8.08 (d, J = 4.5 Hz, 1H), 7.85-7.74 (m, 2H),7.72 (dt, J = 5.4, 1.8 Hz, 1H), 7.52 (dt, J = 1.5, 0.7 Hz, 1H), 7.48(ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.48 (s, 3H). 4-(1-(8-chloro-5- OJ-H1^(st) 135 481.1 1H NMR (400 MHz, fluoroquinolin-4- SFC e- DMSO-d6) δ9.42 yl)-2-methyl- 5 uM luting (d, J = 4.5 Hz, 1H), 4-(4H-1,2,4- 21 ×peak 8.71 (dd, J = 5.3, 0.8 triazol-3-yl)- 250 mm Hz, 1H), 8.53 (s,1H-benzo[d] column in 1H), 8.44 (d, J = 1.8 imidazol-6-yl) 30% Hz, 1H),8.39 (dd, picolinonitrile EtOH/ J = 1.9, 0.8 Hz, 1H), CO2 at 8.16-8.11(m, 2H), 60 mL/ 8.08 (dd, J = 5.3, 1.9 min Hz, 1H), 7.89 (d, J = 1.7 Hz,1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H), 2.53 (s, 3H). 2^(nd) 136 481.1 1HNMR (400 MHz, e- DMSO-d6) δ 9.42 luting (d, J = 4.5 Hz, 1H), peak 8.71(dd, J = 5.3, 0.8 Hz, 1H), 8.53 (s, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.39(dd, J = 1.9, 0.8 Hz, 1H), 8.16-8.11 (m, 2H), 8.08 (dd, J = 5.3, 1.9 Hz,1H), 7.89 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 11.9, 8.6 Hz, 1H), 2.53 (s,3H). 8-chloro-4-(6-(3- OJ-H 1^(st) 137 456.1 1H NMR (400 MHz,fluoropyridin- SFC e- DMSO-d6) δ 9.33 4-yl)-2-methyl- 5 uM luting (dd, J= 4.5, 0.6 Hz, 4-(4H-1,2,4- 21 × peak 1H), 8.60 (d, J = 2.6triazol-3-yl)- 250 mm Hz, 1H), 8.51 (s, 1H-benzo[d] column in 1H),8.43-8.39 (m, imidazol-1- 20% 1H), 8.30 (d, J = 1.9 yl)quinoline MeOH/Hz, 1H), 8.11 (dt, CO2 J = 7.4, 1.0 Hz, 1H), at 60 mL/ 8.08 (d, J = 4.5Hz, min 1H), 7.63-7.55 (m, 2H), 7.49 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H),2.54 (s, 3H). 2^(nd) 138 456.1 1H NMR (400 MHz, e- DMSO-d6) δ 9.33luting (dd, J = 4.5, 0.6 Hz, peak 1H), 8.60 (d, J = 2.6 Hz, 1H), 8.51(s, 1H), 8.43-8.39 (m, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.11 (dt, J = 7.4,1.0 Hz, 1H), 8.08 (d, J = 4.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.49 (s, 1H),7.42 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H). 5,8-difluoro-4- OJ-H 1^(st) 139440.2 1H NMR (400 MHz, (2-methyl-6- SFC e- DMSO-d6) δ 9.33 (pyridin-4- 5uM luting (d, J = 4.5 Hz, 1H), yl)-4-(4H- 21 × peak 8.78-8.73 (m, 2H),1,2,4- 250 mm 8.46 (dd, J = 1.8, 0.6 triazol-3-yl)- column Hz, 1H),8.23-8.16 1H-benzo[d] in 30% (m, 2H), 8.09 (d, J = imidazol-1- MeOH/ 4.5Hz, 1H), 7.91 yl)quinoline CO2 (dd, J = 1.8, 0.6 Hz, at 60 mL/ 1H), 7.79(td, J = min 9.5, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.7, 3.8 Hz, 1H),2.50 (s, 3H). 2^(nd) 140 440.1 1H NMR (400 MHz, e- DMSO-d6) δ 9.33luting (d, J = 4.5 Hz, 1H), peak 8.78-8.73 (m, 2H), 8.46 (dd, J = 1.8,0.6 Hz, 1H), 8.23-8.16 (m, 2H), 8.09 (d, J = 4.5 Hz, 1H), 7.91 (dd, J =1.8, 0.6 Hz, 1H), 7.79 (td, J = 9.5, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3,8.7, 3.8 Hz, 1H), 2.50 (s, 3H). 5,8-difluoro-4- OD-H 1^(st) 141 454.2 1HNMR (400 MHz, (2-methyl-6-(2- SFC e- DMSO-d6) δ 9.34 methylpyridin- 5 uMluting (d, J = 4.5 Hz, 1H), 4-yl)-4-(4H- 21 × peak 8.70 (dd, J = 6.4,0.6 1,2,4-triazol-3- 250 mm Hz, 1H), 8.48 (d, J = yl)-1H-benzo[d] column1.8 Hz, 1H), 8.44 (s, imidazol-1- in 30% 1H), 8.25 (d, J = 1.9yl)quinoline EtOH/ Hz, 1H), 8.15 (dd, CO2 at J = 6.3, 2.0 Hz, 1H), 60mL/ 8.10 (d, J = 4.5 Hz, min 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.79 (ddd, J= 10.0, 8.8, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 2.67(s, 3H), 2.48 (s, 3H). 2^(nd) 142 454.2 1H NMR (400 MHz, e- DMSO-d6) δ9.34 luting (d, J = 4.5 Hz, 1H), peak 8.70 (dd, J = 6.4, 0.6 Hz, 1H),8.48 (d, J = 1.8 Hz, 1H), 8.44 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.15(dd, J = 6.3, 2.0 Hz, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.90 (d, J = 1.8Hz, 1H), 7.79 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3,8.8, 3.8 Hz, 1H), 2.67 (s, 3H), 2.48 (s, 3H).

From the foregoing it will be appreciated that, although specificembodiments have been described herein for purposes of illustration,various modifications may be made without deviating from the spirit andscope of the present application.

Biological Examples

The compounds of formula (I) were characterized for their enzymaticactivity against the PI3K isoforms. The activities were measured using atime-resolved fluorescence resonance energy transfer (TR-FRET) assay.TR-FRET monitored the formation of 3,4,5-inositol triphosphate moleculethat competed with fluorescently labeled PIPS for binding to the GRP-1pleckstrin homology domain protein. An increase in phosphatidylinositide3-phosphate product resulted in a decrease in TR-FRET signal as thelabeled fluorophore was displaced from the GRP-1 protein binding site.

Class I PI3K isoforms were expressed and purified as heterodimericrecombinant proteins. All assay reagents and buffers for the TR-FRETassay were purchased from Millipore. PI3K isoforms were assayed underinitial rate conditions in the presence of 25 mM Hepes (pH 7.4), and 2×Km ATP (75-500 μM), 2 μM PIP2, 5% glycerol, 5 mM MgCl₂, 50 mM NaCl,0.05% (v/v) Chaps, 1 mM dithiothreitol, and 1% (v/v) DMSO at thefollowing concentrations for each isoform: PI3Kα, PI3Kβ, and PI3Kδbetween 25 and 50 pM, and PI3Kγ at 2 nM. The compounds were added to theassay solution and incubated for 30 minutes at 25° C. The reactions wereterminated with a final concentration of 10 mM EDTA, 10 nM labeled-PIPS,and 35 nM Europium labeled GRP-1 detector protein before reading TR-FRETon an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 μs delayand 500 μs read window).

The results were normalized based on positive (1 μM wortmanin) andnegative (DMSO) controls, and the IC₅₀ values for PI3K α, β, δ, and γwere calculated from the fit of the dose-response curves to afour-parameter equation. These assays generally produced results within3-fold of the reported mean.

Compound IC₅₀-PIP-Beta (nM) 1 34 2 13 3 2800 4 20 5 86 6 36 7 16 8 82 9950 10 1600 11 3 12 340 13 15 14 62 15 150 16 51 17 150 18 23 19 12 201100 21 1300 22 1100 23 96 24 22 25 6 26 13 27 5 28 6 29 6 30 8 31 89 326 33 110 34 26 35 22 36 250 37 4 38 7 39 5 40 5 41 27 42 10 43 30 44 445 8 46 1100 47 46 48 10 49 170 50 17 51 3 52 330 53 180 54 36 55 19 569 57 290 58 10 59 270 60 420 61 35 62 8 63 7 64 200 65 16 66 140 67 8 6835 69 47 70 13 71 13 72 10 73 8 74 29 75 3 76 50 77 1400 78 5 79 8 80 281 15 82 120 83 2 84 4 85 3 86 7 87 12 88 110 89 3 90 340 91 19 92 51 935 94 8 95 5 96 7 97 31 98 6 99 29 100 320 101 2800 102 11 103 210 104 9105 1400 106 3 107 29 108 810 109 2600 110 2 111 2500 112 5 113 2 114560 115 3 116 30 117 4 118 35 119 87 120 4 121 1 122 28 123 8 124 160125 110 126 780 127 9 128 360 129 3 130 57 131 2 132 54 133 2 134 400135 4 136 220 137 10 138 99 139 6 140 540 141 120 142 11 143 6 144 18145 2 146 200 147 4 148 16 149 4 150 13 151 80 152 10 153 7 154 9 155 62156 12 157 460 158 7 159 5 160 7 161 6 162 10 163 120 164 10 165 480 16670 167 10

From the foregoing it will be appreciated that, although specificembodiments have been described herein for purposes of illustration,various modifications may be made without deviating from the spirit andscope of the present application.

What is claimed:
 1. A compound having the structure of formula (I):

wherein n is 1, 2, 3 or 4; s is 1 or 2; t is 1 or 2; each R¹ isindependently selected from hydrogen, halo, cyano, hydroxy, amino,—C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),—S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g),—NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4heteroatoms selected from the group consisting of N, O, and S, and 4-10membered heterocyclyl containing 1 to 4 heteroatoms selected from thegroup consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and4-10 membered heterocyclyl is optionally substituted with one to fourR¹⁰⁰; R² is selected from hydrogen, halo, cyano, hydroxy, amino,—C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),—S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R, —NR^(a)R^(b),—OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4heteroatoms selected from the group consisting of N, O, and S, and 4-10membered heterocyclyl containing 1 to 4 heteroatoms selected from thegroup consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and4-10 membered heterocyclyl is optionally substituted with one to fourR¹⁰¹; R³ is selected from hydrogen, halo, cyano, hydroxy, amino,—C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),—N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b),—NR^(a)S(O)₂R^(a), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),—S(O)₂R^(g)—NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroarylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatomsselected from the group consisting of N, O, and S; wherein each C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and 4-10 membered heterocyclyl is optionallysubstituted with one to four R¹⁰²; R⁴ is a 5-10 membered heteroaryl;wherein said 5-10 membered heteroaryl is optionally substituted with oneto four R¹⁰³; each R⁵ is independently selected from hydrogen, halo,cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),—NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a), —S(O)NR^(a)R^(b),—S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a),—SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selectedfrom the group consisting of N, O, and S, and 4-10 membered heterocyclylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 memberedheterocyclyl is optionally substituted with one to four R¹⁰⁴; each R⁶ isindependently hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a),—C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),—S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a),—SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; each R^(a) and R^(b)is independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl andC₂₋₆ alkynyl; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, isoptionally substituted with one to four R²⁰⁰; each R¹⁰⁰, R¹⁰¹, R¹⁰²,R¹⁰³ and R¹⁰⁴ is independently selected from hydrogen, halo, cyano,hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(c), —C(O)OR^(c),—C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d), —N(R^(a))C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(a)S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(a),—S(O)NR^(c)R^(d), —S(O)₂NR^(c)R^(d), —S(O)R^(g), —S(O)₂R^(g),—NR^(c)R^(d), —OR^(c), —SR^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 memberedheterocyclyl; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 memberedheterocyclyl is optionally substituted with one to four R²⁰¹; each R^(c)and R^(d) is independently selected from hydrogen, C₆₋₁₀ aryl, C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; each R²⁰⁰ and R²⁰¹ isindependently selected from hydrogen, halo, cyano, hydroxy, amino, oxo,thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(f),—N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f), —S(O)₂NR^(e)R^(f), —S(O)R^(g),—S(O)₂R^(g), —NR^(e)R^(f), —OR^(e), —SR^(e), C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl; each R^(e) and R^(f) is independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; each R^(g) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4heteroatoms selected from the group consisting of N, O, and S, and 4-10membered heterocyclyl containing 1 to 4 heteroatoms selected from thegroup consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and4-10 membered heterocyclyl is optionally substituted with one to fourR²⁰⁰; or a pharmaceutically acceptable salt, isomer, or a mixturethereof.
 2. The compound of claim 1 having the structure of formula IA:

wherein n, s, t, R¹, R², R⁴, R⁵ and R⁶ are as defined in claim 1; X¹ isN or C; each X², X³, X⁴ and X⁵ is independently selected from S, O, CR¹⁰and NR¹¹; wherein each R¹⁰ is independently selected from hydrogen,halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),—N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),—S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroarylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatomsselected from the group consisting of N, O, and S; wherein each C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and 4-10 membered heterocyclyl is optionallysubstituted with one to four R²⁰¹; wherein each R¹¹ is independentlyselected from absent, hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a),—C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),—S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a),—SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selectedfrom the group consisting of N, O, and S, and 4-10 membered heterocyclylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S; or one R¹⁰ and one R¹¹ group, together with the atoms to whichthey are attached form a five, six or seven membered fused, or bridgedring; or a pharmaceutically acceptable salt, isomer, or a mixturethereof.
 3. The compound of claim 1, wherein R³ is selected from:

wherein t is 1 or 2; wherein each R¹³ is independently selected fromhydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b),—C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),—S(O)₂NR^(a)R^(b), —S(O)R^(g), —S(O)₂R^(g), —NR^(a)R^(b), —OR^(a),—SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selectedfrom the group consisting of N, O, and S, and 4-10 membered heterocyclylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S; or a pharmaceutically acceptable salt, isomer, or a mixturethereof.
 4. The compound of claim 1 having the structure of formula IB:

wherein each R¹³ is independently selected from hydrogen, halo, cyano,hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),—N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),—S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroarylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatomsselected from the group consisting of N, O, and S; or a pharmaceuticallyacceptable salt, isomer, or a mixture thereof.
 5. The compound of claim1 having the structure of formula IC:

wherein each R¹³ is independently selected from hydrogen, halo, cyano,hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),—N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),—S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroarylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatomsselected from the group consisting of N, O, and S; or a pharmaceuticallyacceptable salt, isomer, or a mixture thereof.
 6. The compound of claim2 having the structure of formula ID:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 7.The compound of claim 1 having the structure of formula IE:

wherein each R¹³ is independently selected from hydrogen, halo, cyano,hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),—N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),—S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroarylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatomsselected from the group consisting of N, O, and S; or a pharmaceuticallyacceptable salt, isomer, or a mixture thereof.
 8. The compound of claim3 having the structure of formula IF:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 9.The compound of claim 2 having the structure of formula IG:

or a pharmaceutically acceptable salt thereof; wherein the atropisomerof formula IE or a pharmaceutically acceptable salt thereof, is presentin excess of its corresponding enantiomer or a pharmaceuticallyacceptable salt thereof.
 10. The compound of claim 3 having thestructure of formula IH:

wherein each R¹³ is independently selected from hydrogen, halo, cyano,hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),—N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(g),—S(O)₂R^(g), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroarylcontaining 1 to 4 heteroatoms selected from the group consisting of N,O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatomsselected from the group consisting of N, O, and S; or a pharmaceuticallyacceptable salt, isomer, or a mixture thereof.
 11. The compound of claim3 having the structure of formula IJ:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 12.The compound of claim 1, wherein R⁴ is selected from the groupconsisting of:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 13.The compound of claim 1, wherein R¹ is selected from hydrogen, fluoro,chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl,difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl andtrifluoroethyl; or a pharmaceutically acceptable salt, isomer, or amixture thereof.
 14. The compound of claim 1, wherein R² is C₁₋₆ alkyl,C₃₋₈ cycloalkyl, 5-6 membered heteroaryl containing 1 to 3 heteroatomsselected from the group consisting of N, O, and S, and 4-6 memberedheterocyclyl containing 1 to 4 heteroatoms selected from the groupconsisting of N, O, and S; wherein each C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocyclyl is optionallysubstituted with one to four R¹⁰¹; or a pharmaceutically acceptablesalt, isomer, or a mixture thereof.
 15. The compound of claim 1, whereinR³ is selected from 5-10 membered heteroaryl containing 1 to 4heteroatoms selected from the group consisting of N, O, and S, —C(O)OH,and —C(O)NH₂; or a pharmaceutically acceptable salt, isomer, or amixture thereof.
 16. The compound of claim 1, wherein R⁵ is selectedfrom hydrogen, methyl, ethyl, trifluoromethyl, carboxamide, cyano,piperazinyl, cyclopropyl, phenyl and triazolyl; or a pharmaceuticallyacceptable salt, isomer, or a mixture thereof.
 17. The compound of claim1, wherein the compound is selected from: Example Structure 1

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or a pharmaceutically acceptable salt, isomer, or a mixture thereof. 18.A pharmaceutical composition comprising the compound according to claim1, or a pharmaceutically acceptable salt, isomer, or a mixture thereof,and at least one pharmaceutically acceptable vehicle.
 19. A tabletcomprising the compound of claim 1, or a pharmaceutically acceptablesalt, isomer, or a mixture thereof, and a pharmaceutically acceptablecarrier.